TWI803482B - Farnesoid x receptor agonists and uses thereof - Google Patents

Farnesoid x receptor agonists and uses thereof Download PDF

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TWI803482B
TWI803482B TW107108918A TW107108918A TWI803482B TW I803482 B TWI803482 B TW I803482B TW 107108918 A TW107108918 A TW 107108918A TW 107108918 A TW107108918 A TW 107108918A TW I803482 B TWI803482 B TW I803482B
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尼可拉斯 Ｄ 史密斯
史堤分 Ｐ 戈衛克
長澤強尼Ｙ
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美商梅塔克林公司
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Abstract

Described herein are compounds that are farnesoid X receptor agonists, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with farnesoid X receptor activity.

Description

法尼醇X受體促效劑及其用途Farnesoid X receptor agonists and uses thereof

本文描述作為法尼醇X受體促效劑之化合物；製造此類化合物之方法；包含此類化合物之醫藥組合物及藥劑；及使用此類化合物在治療與法尼醇X受體活性相關聯之病狀、疾病或病症之方法。Described herein are compounds that are agonists of the farnesoid X receptor; methods of making such compounds; pharmaceutical compositions and medicaments comprising such compounds; and the use of such compounds in the treatment of compounds associated with farnesoid X receptor activity. The condition, disease or disease of the disease.

法尼醇X受體(FXR)為在肝臟、腸、腎臟、腎上腺及脂肪組織中高度表現之核受體。FXR會調節與膽汁酸合成及輸送、脂質代謝及葡萄糖內穩定之控制有關的多種靶基因。FXR促效作用為針對多種代謝障礙、肝臟疾病或病狀、發炎性病狀、胃腸疾病或細胞增殖疾病之治療模態。Farnesoid X receptor (FXR) is a nuclear receptor highly expressed in liver, intestine, kidney, adrenal gland and adipose tissue. FXR regulates a variety of target genes involved in the control of bile acid synthesis and transport, lipid metabolism, and glucose homeostasis. FXR agonism is a therapeutic modality for a variety of metabolic disorders, liver diseases or conditions, inflammatory conditions, gastrointestinal diseases or cell proliferative diseases.

在一個態樣中，本文描述法尼醇X受體促效劑及其用途。在一個態樣中，本文描述具有式(I)結構之化合物或其醫藥學上可接受之鹽或溶劑合物：

Figure 02_image003
式(I) 其中， X1 為CH或N； R1 為H、D、鹵素、-CN、-OH、-SH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-S(C1 -C4 烷基)、-S(=O)(C1 -C4 烷基)、-S(=O)2 (C1 -C4 烷基)、-S(=O)2 N(R15 )2 、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-C(=O)N(R15 )2 、-NR15 C(=O)(C1 -C4 烷基)、-NR15 C(=O)O(C1 -C4 烷基)、-OC(=O)N(R15 )2 、-NR15 C(=O)N(R15 )2 、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基、C1 -C4 雜烷基或經取代或未經取代之單環C2 -C5 雜環烷基； X2 為CR2 或N； R2 為H、D、鹵素、-CN、-OH、-SH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-S(C1 -C4 烷基)、-S(=O)(C1 -C4 烷基)、-S(=O)2 (C1 -C4 烷基)、-S(=O)2 N(R15 )2 、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-C(=O)N(R15 )2 、-NR15 C(=O)(C1 -C4 烷基)、-NR15 C(=O)O(C1 -C4 烷基)、-OC(=O)N(R15 )2 、-NR15 C(=O)N(R15 )2 、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基或C1 -C4 雜烷基或經取代或未經取代之單環C2 -C5 雜環烷基； 或R1 及R2 與插入原子一起形成經取代或未經取代之5員稠環或經取代或未經取代之6員稠環，在該環中具有0至3個N原子及0至2個O或S原子； X3 為CR3 或N； R3 為H、D、鹵素、-CN、-OH、-SH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-S(C1 -C4 烷基)、-S(=O)(C1 -C4 烷基)、-S(=O)2 (C1 -C4 烷基)、-S(=O)2 N(R15 )2 、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-C(=O)N(R15 )2 、-NR15 C(=O)(C1 -C4 烷基)、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基、C1 -C4 雜烷基或經取代或未經取代之單環C2 -C5 雜環烷基； 各X4 獨立地為CH或N； R4 為H、D、F或-CH3 ； R5 為H、D、F或-CH3 ； 或R4 及R5 一起形成橋鍵，其為-CH2 -或-CH2 CH2 -； 各R6 獨立地為H、D、F、-OH或-CH3 ； m為0、1或2； R7 為H、D、鹵素、-CN、-OH、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基或C1 -C4 雜烷基； L不存在、為-Y2 -L1 -、-L1 -Y2 -、伸環丙基、伸環丁基或雙環[1.1.1]伸戊基； Y2 不存在、為-O-、-S-、-S(=O)-、-S(=O)2 -、-S(=O)2 NR15 -、-CH2 -、-CH=CH-、-C≡C-、-C(=O)-、-C(=O)O-、-OC(=O)-、-OC(=O)O-、-C(=O)NR15 -、-NR15 C(=O)-、-OC(=O)NR15 -、-NR15 C(=O)O-、-NR15 C(=O)NR15 -、-NR15 S(=O)2 -或-NR15 -； L1 不存在或為經取代或未經取代之C1 -C4 伸烷基； X5 為NR8 或N； R8 為H、D、C1 -C6 烷基、C1 -C6 氘代烷基、C1 -C6 氟烷基、C1 -C6 雜烷基、-C(=O)(C1 -C4 烷基)、-CO2 (C1 -C4 烷基)、-C(=O)N(R15 )2 、-S(=O)2 (C1 -C4 烷基)、-S(=O)2 N(R15 )2 、經取代或未經取代之C3 -C6 環烷基或經取代或未經取代之單環C2 -C6 雜環烷基、經取代或未經取代之苯基或經取代或未經取代之單環雜芳基； R9 為H、D、F或-CH3 ； Y為-CR10 R11 -、-O-、-S-、-S(=O)-、-S(=O)2- 或-NR17 -； R10 為H、D、鹵素、-CN、-OH、C1 -C6 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C6 烷氧基、C1 -C6 氟烷基、-SR12 、-S(=O)R14 、-S(=O)2 R14 、或-N(R12 )2 ； R11 為H、D、F或-CH3 ； 或R9 及R11 一起形成橋鍵，其為-CH2 -或-CH2 CH2 -； 各R12 獨立地為H、C1 -C4 烷基、C1 -C4 氘代烷基、C1 -C4 氟烷基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之C2 -C6 雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基、經取代或未經取代之單環雜芳基； R14 為C1 -C4 烷基、C1 -C4 氘代烷基、C1 -C4 氟烷基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之C2 -C6 雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基或經取代或未經取代之單環雜芳基； R15 為H或經取代或未經取代之C1 -C6 烷基； 各R16 獨立地為H、D、鹵素、-CN、-OH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-S(C1 -C4 烷基)、-S(=O)(C1 -C4 烷基)、-S(=O)2 (C1 -C4 烷基)、-C(=O)(C1 -C4 烷基)、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-NR15 C(=O)(C1 -C4 烷基)、-C(=O)N(R15 )2 、-NR15 C(=O)O(C1 -C4 烷基)、-OC(=O)N(R15 )2 、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之單環C2 -C6 雜環烷基、經取代或未經取代之苯基或經取代或未經取代之單環雜芳基； n為0、1或2； R17 為-L5 -R14 ；及 L5 不存在、為-S(=O)2 -、-C(=O)-、-CO2 -或-C(=O)N(R15 )-。 上文針對各種變數所述之基團的任何組合涵蓋於本文中。在整個說明書中，熟習此領域者會選擇基團及其取代基以得到穩定部分及化合物。在一個態樣中，本文描述一種包含本文所述之化合物或其醫藥學上可接受之鹽或溶劑合物，及至少一種醫藥學上可接受之賦形劑的醫藥組合物。在一些實施例中，醫藥組合物調配用於藉由靜脈內投藥、皮下投藥、口服、吸入、經鼻投藥、真皮投藥或經眼投藥來向哺乳動物投與。在一些實施例中，醫藥組合物調配用於藉由靜脈內投藥、皮下投藥或口服向哺乳動物投與。在一些實施例中，醫藥組合物調配用於藉由口服向哺乳動物投與。在一些實施例中，醫藥組合物呈以下形式：錠劑、丸劑、膠囊、液體、懸浮液、凝膠、分散液、溶液、乳液、軟膏或洗劑。在一些實施例中，醫藥組合物呈錠劑、丸劑或膠囊形式。 在另一態樣中，本文描述一種治療哺乳動物中之疾病或病狀的方法，該哺乳動物將受益於FXR促效作用，該方法包含向有需要之哺乳動物投與如本文所述之化合物或其醫藥學上可接受之鹽或溶劑合物。在一些實施例中，疾病或病狀為代謝病狀。在一些實施例中，疾病或病狀為肝臟病狀。 在一些實施例中，藉由靜脈內投藥、皮下投藥、口服、吸入、經鼻投藥、真皮投藥或經眼投藥來向哺乳動物投與化合物。 在一個態樣中，本文描述一種治療或預防本文所述之疾病或病狀中之任一者的方法，該方法包含向有需要之哺乳動物投與治療有效量之本文所述之化合物或其醫藥學上可接受之鹽或溶劑合物。 在一個態樣中，本文描述一種治療或預防哺乳動物中之代謝或肝臟病狀的方法，該方法包含向有需要之哺乳動物投與治療有效量之本文所述之化合物或其醫藥學上可接受之鹽或溶劑合物。在其他實施例中，代謝或肝臟病狀適合於用FXR促效劑治療。在一些實施例中，除了本文所述之化合物或其醫藥學上可接受之鹽或溶劑合物之外，該方法進一步包含向哺乳動物投與第二治療劑。 在一個態樣中，本文描述一種治療或預防哺乳動物中之肝臟疾病或病狀的方法，該方法包含向哺乳動物投與式(I)化合物或其醫藥學上可接受之鹽或溶劑合物。在一些實施例中，肝臟疾病或病狀為酒精性或非酒精性肝臟疾病。在一些實施例中，肝臟疾病或病狀為原發性膽汁性肝硬化症、原發性硬化性膽管炎、膽汁鬱積、非酒精性脂肪變性肝炎(NASH)或非酒精性脂肪肝病(NAFLD)。在一些實施例中，酒精性肝臟疾病或病狀為脂肪肝(脂肪變性)、肝硬化症或酒精性肝炎。在一些實施例中，非酒精性肝臟疾病或病狀為非酒精性脂肪變性肝炎(NASH)或非酒精性脂肪肝病(NAFLD)。在一些實施例中，非酒精性肝臟疾病或病狀為非酒精性脂肪變性肝炎(NASH)。在一些實施例中，非酒精性肝臟疾病或病狀為非酒精性脂肪變性肝炎(NASH)且伴有肝纖維化。在一些實施例中，非酒精性肝臟疾病或病狀為不存在肝纖維化之非酒精性脂肪變性肝炎(NASH)。在一些實施例中，非酒精性肝臟疾病或病狀為肝內膽汁鬱積或肝外膽汁鬱積。 在一個態樣中，本文描述一種治療或預防哺乳動物中之肝纖維化的方法，該方法包含向哺乳動物投與式(I)化合物或其醫藥學上可接受之鹽或溶劑合物。在一些實施例中，該哺乳動物診斷患有C型肝炎病毒(HCV)、非酒精性脂肪變性肝炎(NASH)、原發性硬化性膽管炎(PSC)、肝硬化症、威爾遜氏病(Wilson's disease)、B型肝炎病毒(HBV)、HIV相關聯之脂肪變性肝炎及肝硬化症、慢性病毒性肝炎、非酒精性脂肪肝病(NAFLD)、酒精性脂肪變性肝炎(ASH)、非酒精性脂肪變性肝炎(NASH)、原發性膽汁性肝硬化症(PBC)或膽汁性肝硬化症。在一些實施例中，該哺乳動物診斷患有非酒精性脂肪變性肝炎(NASH)。 在一個態樣中，本文描述一種治療或預防哺乳動物中之肝炎的方法，該方法包含向哺乳動物投與式(I)化合物或其醫藥學上可接受之鹽或溶劑合物。在一些實施例中，該哺乳動物診斷患有C型肝炎病毒(HCV)、非酒精性脂肪變性肝炎(NASH)、原發性硬化性膽管炎(PSC)、肝硬化症、威爾遜氏病、B型肝炎病毒(HBV)、HIV相關聯之脂肪變性肝炎及肝硬化症、慢性病毒性肝炎、非酒精性脂肪肝病(NAFLD)、酒精性脂肪變性肝炎(ASH)、非酒精性脂肪變性肝炎(NASH)、原發性膽汁性肝硬化症(PBC)或膽汁性肝硬化症。在一些實施例中，該哺乳動物診斷患有非酒精性脂肪變性肝炎(NASH)。在一些實施例中，肝炎與胃腸道中之炎症相關聯。在一些實施例中，該哺乳動物診斷患有發炎性腸病。 在一個態樣中，本文描述一種治療或預防哺乳動物中之胃腸疾病或病狀的方法，該方法包含向哺乳動物投與式(I)化合物或其醫藥學上可接受之鹽或溶劑合物。在一些實施例中，胃腸疾病或病狀為壞死性小腸結腸炎、胃炎、潰瘍性結腸炎、克羅恩氏病(Crohn's disease)、發炎性腸病、大腸急躁症、胃腸炎、輻射誘發腸炎、偽膜性結腸炎、化學療法誘發腸炎、胃-食道逆流病(GERD)、消化性潰瘍、非潰瘍性消化不良(NUD)、乳糜瀉、腸道乳糜瀉、術後炎症、胃癌發生、移植物抗宿主疾病或其任何組合。在一些實施例中，胃腸疾病為大腸急躁症(IBS)、伴隨腹瀉之大腸急躁症(IBS-D)、伴隨便秘之大腸急躁症(IBS-C)、混合型IBS (IBS-M)、未定型IBS (IBS-U)或膽汁酸腹瀉(BAD)。 在一個態樣中，本文描述一種治療或預防哺乳動物中之疾病或病狀的方法，該哺乳動物將受益於用FXR促效劑進行之治療，該方法包含向哺乳動物投與式(I)化合物或其醫藥學上可接受之鹽或溶劑合物。在一些實施例中，除了式(I)化合物或其醫藥學上可接受之鹽或溶劑合物之外，本文所述之方法進一步包含投與至少一種額外治療劑。 前述態樣中之任一者為將有效量之本文所述之化合物或其醫藥學上可接受之鹽：(a)全身性地投與哺乳動物；及/或 (b)經口投與哺乳動物；及/或(c)靜脈內投與哺乳動物；及/或(d)藉由吸入投與；及/或(e)藉由經鼻投藥投與；及/或(f)藉由注射投與哺乳動物；及/或(g)表面投與哺乳動物；及/或(h)藉由經眼投藥投與；及/或(i)經直腸投與哺乳動物；及/或(j)非全身性地或局部投與哺乳動物之其他實施例。 前述態樣中之任一者中為包含單次投與有效量之化合物的其他實施例，其包括其中向哺乳動物投與化合物一日一次或在一天內向哺乳動物投與化合物多次的其他實施例。在一些實施例中，以連續給藥時程投與化合物。在一些實施例中，以連續每日給藥時程投與化合物。 涉及治療疾病或病狀的前述態樣中之任一者為包含除了投與本文所述之式(I)化合物或其醫藥學上可接受之鹽之外，投與至少一種額外藥劑之其他實施例。在各種實施例中，以任何次序投與各藥劑，包括同時投與。 在本文所揭示之任何實施例中，哺乳動物或個體為人類。 在一些實施例中，本文中所提供之化合物係向人類投與。 在一些實施例中，本文中所提供之化合物係經口投與。 在一些實施例中，本文描述一種治療或預防個體中之代謝障礙的方法，該方法包含：向個體之胃腸道投與治療有效量之本文所述之化合物中之一或多者，或其醫藥學上可接受之鹽或溶劑合物，由此在腸中活化法尼醇X受體(FXR)，且治療或預防個體中之代謝障礙。在一些實施例中，化合物之吸收優先限於腸內。在一些實施例中，該方法實質上增強腸中之FXR靶基因表現，同時並不會實質上增強肝臟或腎臟中之FXR靶基因表現。在一些實施例中，該方法實質上增強腸中之FXR靶基因表現，同時將所遞送化合物之全身血漿水準降至最低。在一些實施例中，該方法實質上增強腸及肝臟中之FXR靶基因表現，同時將所遞送化合物之全身血漿水準降至最低。在一些實施例中，該方法實質上增強腸中之FXR靶基因表現，同時並不會實質上增強肝臟或腎臟中之FXR靶基因表現，且同時將全身血漿水準降至最低。在一些實施例中，該方法實質上增強腸及肝臟中之FXR靶基因表現，且提供所遞送化合物之持續全身血漿水準。在一些實施例中，該方法減少或預防飲食誘發之體重增加。在一些實施例中，該方法提高個體中之代謝速率。在一些實施例中，增加代謝速率包含增強個體中之氧化磷酸化。在一些實施例中，該方法進一步包含改良個體中之葡萄糖及/或脂質內穩定。在一些實施例中，該方法並未引起個體中之攝食量及/或脂肪消耗量發生實質變化。在一些實施例中，該方法並未引起個體中之食慾發生實質變化。在一些實施例中，代謝障礙係選自肥胖、糖尿病、胰島素抗性、血脂異常或其任何組合。在一些實施例中，代謝障礙為非胰島素依賴性糖尿病。在一些實施例中，該方法保護免受飲食誘發之體重增加、減少炎症、增強生熱作用、增強肝臟中之胰島素敏感度、降低肝脂肪變性、促進BAT活化、降低血糖、增加體重減輕或其任何組合。在一些實施例中，該方法增強肝臟中之胰島素敏感度且促進棕色脂肪組織(BAT)活化。在一些實施例中，該方法進一步包含向個體投與胰島素敏化藥物、胰島素促泌素、α-葡糖苷酶抑制劑、類升糖素肽(GLP)促效劑、二肽基肽酶-4 (DPP-4)抑制劑、菸鹼醯胺核苷、菸鹼醯胺核苷之類似物或其組合。 在一些實施例中，本文描述一種治療或預防個體之腸道區域中的炎症之方法，該方法包含：向個體之胃腸道投與治療有效量之本文所述之化合物中之一或多者，或其醫藥學上可接受之鹽或溶劑合物，由此在腸中活化FXR受體，且由此治療或預防個體之腸區域中的炎症。在一些實施例中，化合物之吸收優先限於腸內。在一些實施例中，該方法實質上增強腸中之FXR靶基因表現，同時並不會實質上增強肝臟或腎臟中之FXR靶基因表現。在一些實施例中，炎症與選自以下之臨床病狀相關聯：壞死性小腸結腸炎、胃炎、潰瘍性結腸炎、克羅恩氏病、發炎性腸病、大腸急躁症、胃腸炎、輻射誘發腸炎、偽膜性結腸炎、化學療法誘發腸炎、胃-食道逆流病(GERD)、消化性潰瘍、非潰瘍性消化不良(NUD)、乳糜瀉、腸道乳糜瀉、術後炎症、胃癌發生或其任何組合。在一些實施例中，一或多種FXR靶基因包含IBABP、OSTα、Per1、FGF15、FGF19、SHP或其組合。在一些實施例中，方法進一步包含向個體投與治療有效量之抗生素療法，其中該方法治療或預防個體中的與偽膜性結腸炎相關聯之炎症。在一些實施例中，該方法進一步包含向個體投與治療有效量之口服皮質類固醇、其他消炎或免疫調節療法、菸鹼醯胺核苷、菸鹼醯胺核苷之類似物或其組合。在一些實施例中，該方法增加HSL磷酸化及β3-腎上腺素激導性受體表現。在一些實施例中，在投與化合物後，個體中的化合物之血清濃度保持低於其EC50 。 在一些實施例中，本文描述一種治療或預防個體中之細胞增殖疾病的方法，該方法包含向個體之胃腸道投與治療有效量之本文所述之化合物中之一或多者，或其醫藥學上可接受之鹽或溶劑合物。在一些實施例中，細胞增殖疾病為腺癌。在一些實施例中，腺癌為結腸癌。在一些實施例中，治療腺癌會減小腺癌尺寸、腺癌體積、腺癌數目、由腺癌導致之惡病質；延遲腺癌進展；增加個體存活期或其組合。在一些實施例中，該方法進一步包含向個體投與額外治療性化合物，其係選自由以下組成之群：化學治療劑、生物製劑、放射性治療劑或其組合。 在一些實施例中，本文描述一種治療或預防個體中之肝臟疾病或病狀的方法，該方法包含向個體投與治療有效量之本文所述之化合物中之一或多者，或其醫藥學上可接受之鹽或溶劑合物。在一些實施例中，肝臟疾病或病狀為酒精性或非酒精性肝臟疾病。在一些實施例中，肝臟疾病或病狀為原發性膽汁性肝硬化症、原發性硬化性膽管炎、膽汁鬱積、非酒精性脂肪變性肝炎(NASH)或非酒精性脂肪肝病(NAFLD)。在一些實施例中，酒精性肝臟疾病或病狀為脂肪肝(脂肪變性)、肝硬化症或酒精性肝炎。在一些實施例中，非酒精性肝臟疾病或病狀為非酒精性脂肪變性肝炎(NASH)或非酒精性脂肪肝病(NAFLD)。在一些實施例中，非酒精性肝臟疾病或病狀為肝內膽汁鬱積或肝外膽汁鬱積。 提供製品，其包括封裝材料；處於封裝材料中之本文所述之化合物或其醫藥學上可接受之鹽；及標籤，其指示化合物或組合物或其醫藥學上可接受之鹽、醫藥活性代謝物、醫藥學上可接受之前藥或醫藥學上可接受之溶劑合物用於治療、預防或改善將受益於FXR促效作用之疾病或病狀的一或多種症狀。自以下實施方式，本文所述之化合物、方法及組合物之其他目標、特徵及優點將變得顯而易見。然而，應理解，實施方式及特定實例儘管指示特定實施例，但僅作為說明而給出，因為對於熟習此項技術者，根據此實施方式本發明精神及範疇內之各種變化及修改將變得顯而易見。In one aspect, described herein are farnesoid X receptor agonists and uses thereof. In one aspect, described herein is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image003
Formula (I) wherein, X 1 is CH or N; R 1 is H, D, halogen, -CN, -OH, -SH, -N(R 15 ) 2 , -NR 15 S(=O) 2 (C 1 -C 4 alkyl), -S(C 1 -C 4 alkyl), -S(=O)(C 1 -C 4 alkyl), -S(=O) 2 (C 1 -C 4 alkyl radical), -S(=O) 2 N(R 15 ) 2 , -OC(=O)(C 1 -C 4 alkyl), -CO 2 H, -CO 2 (C 1 -C 4 alkyl) , -C(=O)N(R 15 ) 2 , -NR 15 C(=O)(C 1 -C 4 alkyl), -NR 15 C(=O)O(C 1 -C 4 alkyl) , -OC(=O)N(R 15 ) 2 , -NR 15 C(=O)N(R 15 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 Alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuterated alkyl, C 1 -C 4 deuterated alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy group, C 1 -C 4 heteroalkyl or substituted or unsubstituted monocyclic C 2 -C 5 heterocycloalkyl; X 2 is CR 2 or N; R 2 is H, D, halogen, -CN, -OH, -SH, -N(R 15 ) 2 , -NR 15 S(=O) 2 (C 1 -C 4 alkyl), -S(C 1 -C 4 alkyl), -S(=O )(C 1 -C 4 alkyl), -S(=O) 2 (C 1 -C 4 alkyl), -S(=O) 2 N(R 15 ) 2 , -OC(=O)(C 1 -C 4 alkyl), -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -C(=O)N(R 15 ) 2 , -NR 15 C(=O)(C 1 -C 4 alkyl), -NR 15 C(=O)O(C 1 -C 4 alkyl), -OC(=O)N(R 15 ) 2 , -NR 15 C(=O)N(R 15 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuterated alkyl, C 1 - C 4 deuterated alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy or C 1 -C 4 heteroalkyl or substituted or unsubstituted monocyclic C 2 -C 5 Heterocycloalkyl; or R and R together with the intervening atom form a substituted or unsubstituted 5-membered fused ring or a substituted or unsubstituted 6-membered fused ring having 0 to 3 N in the ring atom and 0 to 2 O or S atoms; X 3 is CR 3 or N; R 3 is H, D, halogen, -CN, -OH, -SH, -N(R 15 ) 2 , -NR 15 S( =O) 2 (C 1 -C 4 alkyl), -S(C 1 -C 4 alkyl), -S(=O)(C 1 -C 4 alkyl), -S(=O) 2 ( C 1 -C 4 alkyl), -S(=O) 2 N(R 15 ) 2 , -OC(=O)(C 1 -C 4 alkyl), -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -C(=O)N(R 15 ) 2 , -NR 15 C(=O)(C 1 -C 4 alkyl), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuterated alkyl, C 1 -C 4 deuterated alkoxy, C 1 -C 4 fluoroalkyl , C 1 -C 4 fluoroalkoxy, C 1 -C 4 heteroalkyl or substituted or unsubstituted monocyclic C 2 -C 5 heterocycloalkyl; each X 4 is independently CH or N; R 4 is H, D, F or -CH 3 ; R 5 is H, D, F or -CH 3 ; or R 4 and R 5 together form a bridge bond, which is -CH 2 - or -CH 2 CH 2 -; Each R 6 is independently H, D, F, -OH or -CH 3 ; m is 0, 1 or 2; R 7 is H, D, halogen, -CN, -OH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuterated alkyl, C 1 -C 4 deuterated alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy or C 1 -C 4 heteroalkyl; L does not exist, is -Y 2 -L 1 -, -L 1 -Y 2 -, cyclopropyl, Cyclobutyl or bicyclo[1.1.1]pentyl; Y 2 does not exist, is -O-, -S-, -S(=O)-, -S(=O) 2 -, -S(= O) 2 NR 15 -, -CH 2 -, -CH=CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, - OC(=O)O-, -C(=O)NR 15 -, -NR 15 C(=O)-, -OC(=O)NR 15 -, -NR 15 C(=O)O-, - NR 15 C(=O)NR 15 -, -NR 15 S(=O) 2 - or -NR 15 -; L 1 is absent or is substituted or unsubstituted C 1 -C 4 alkylene; X 5 is NR 8 or N; R 8 is H, D, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, -C(=O)(C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), -C(=O)N(R 15 ) 2 , -S(=O) 2 ( C 1 -C 4 alkyl), -S(=O) 2 N(R 15 ) 2 , substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; R 9 is H, D, F or -CH 3 ; Y is -CR 10 R 11 -, -O-, -S-, -S(=O)-, -S(=O) 2- or -NR 17 -; R 10 is H, D, halogen, -CN, -OH, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkyl, -SR 12 , -S(=O) R 14 , -S(=O) 2 R 14 , or -N(R 12 ) 2 ; R 11 is H, D, F or -CH 3 ; or R 9 and R 11 together form a bridge bond, which is -CH 2 - or -CH 2 CH 2 -; each R 12 is independently H, C 1 -C 4 alkyl, C 1 -C 4 deuterated alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 Heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or Unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl; R 14 is C 1 -C 4 alkyl, C 1 -C 4 deuterated alkyl, C 1 -C 4 fluoroalkyl , C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted Phenyl, substituted or unsubstituted benzyl or substituted or unsubstituted monocyclic heteroaryl; R 15 is H or substituted or unsubstituted C 1 -C 6 alkyl; each R 16 independently H, D, halogen, -CN, -OH, -N(R 15 ) 2 , -NR 15 S(=O) 2 (C 1 -C 4 alkyl), -S(C 1 -C 4 Alkyl), -S(=O)(C 1 -C 4 Alkyl), -S(=O) 2 (C 1 -C 4 Alkyl), -C(=O)(C 1 -C 4 Alkyl radical), -OC(=O)(C 1 -C 4 alkyl), -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -NR 15 C(=O)(C 1 -C 4 alkyl), -C(=O)N(R 15 ) 2 , -NR 15 C(=O)O(C 1 -C 4 alkyl), -OC(=O)N(R 15 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuterated alkyl, C 1 -C 4 deuterated Alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted Or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; n is 0, 1 or 2; R 17 is -L 5 -R 14 ; and L 5 is absent, is -S(=O) 2 -, -C(=O)-, -CO 2 - or -C(=O)N(R 15 )-. Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be selected by one skilled in the art to result in stable moieties and compounds. In one aspect, described herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, pharmaceutical compositions are formulated for administration to mammals by intravenous administration, subcutaneous administration, or oral administration. In some embodiments, pharmaceutical compositions are formulated for oral administration to a mammal. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill or capsule. In another aspect, described herein is a method of treating a disease or condition in a mammal that would benefit from FXR agonism, the method comprising administering to the mammal in need thereof a compound as described herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease or condition is a metabolic condition. In some embodiments, the disease or condition is a liver condition. In some embodiments, the compound is administered to the mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In one aspect, described herein is a method of treating or preventing any of the diseases or conditions described herein, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound described herein, or Pharmaceutically acceptable salts or solvates. In one aspect, described herein is a method of treating or preventing a metabolic or hepatic condition in a mammal, the method comprising administering to the mammal in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable Accepted salts or solvates. In other embodiments, the metabolic or hepatic condition is amenable to treatment with an FXR agonist. In some embodiments, the method further comprises administering to the mammal a second therapeutic agent in addition to a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In one aspect, described herein is a method of treating or preventing a liver disease or condition in a mammal, the method comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof . In some embodiments, the liver disease or condition is alcoholic or non-alcoholic liver disease. In some embodiments, the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD) . In some embodiments, the alcoholic liver disease or condition is fatty liver (steatosis), cirrhosis, or alcoholic hepatitis. In some embodiments, the nonalcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD). In some embodiments, the nonalcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH). In some embodiments, the nonalcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH) with liver fibrosis. In some embodiments, the nonalcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH) in the absence of liver fibrosis. In some embodiments, the nonalcoholic liver disease or condition is intrahepatic cholestasis or extrahepatic cholestasis. In one aspect, described herein is a method of treating or preventing liver fibrosis in a mammal, the method comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the mammal is diagnosed with hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, Wilson's disease (Wilson's disease), hepatitis B virus (HBV), HIV-associated steatohepatitis and cirrhosis, chronic viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic steatosis hepatitis (ASH), nonalcoholic steatosis Hepatitis (NASH), primary biliary cirrhosis (PBC), or biliary cirrhosis. In some embodiments, the mammal is diagnosed with non-alcoholic steatohepatitis (NASH). In one aspect, described herein is a method of treating or preventing hepatitis in a mammal, the method comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the mammal is diagnosed with hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, Wilson's disease, B Hepatitis virus (HBV), HIV-associated steatohepatitis and cirrhosis, chronic viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH) , primary biliary cirrhosis (PBC) or biliary cirrhosis. In some embodiments, the mammal is diagnosed with non-alcoholic steatohepatitis (NASH). In some embodiments, hepatitis is associated with inflammation in the gastrointestinal tract. In some embodiments, the mammal is diagnosed with inflammatory bowel disease. In one aspect, described herein is a method of treating or preventing a gastrointestinal disease or condition in a mammal, the method comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof . In some embodiments, the gastrointestinal disease or condition is necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel disorder, gastroenteritis, radiation-induced enteritis , pseudomembranous colitis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, postoperative inflammation, gastric carcinogenesis, graft Anti-host disease or any combination thereof. In some embodiments, the gastrointestinal disorder is irritable bowel syndrome (IBS), irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M), undetermined type IBS (IBS-U) or bile acid diarrhea (BAD). In one aspect, described herein is a method of treating or preventing a disease or condition in a mammal that would benefit from treatment with an FXR agonist, the method comprising administering to the mammal a formula (I) A compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods described herein further comprise administering at least one additional therapeutic agent in addition to a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. Any of the foregoing aspects is administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof: (a) systemically to a mammal; and/or (b) orally administered to a lactation and/or (c) intravenous administration to mammals; and/or (d) administration by inhalation; and/or (e) administration by nasal administration; and/or (f) administration by injection and/or (g) topical administration to a mammal; and/or (h) administration by ophthalmic administration; and/or (i) rectal administration to a mammal; and/or (j) Other embodiments are administered to mammals other than systemically or locally. In any of the foregoing aspects are other embodiments comprising a single administration of an effective amount of the compound, including other embodiments wherein the compound is administered to the mammal once a day or the compound is administered to the mammal multiple times in a day example. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule. Any of the preceding aspects directed to treating a disease or condition is a practice comprising administering at least one additional agent in addition to the compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof. example. In various embodiments, the agents are administered in any order, including simultaneous administration. In any of the embodiments disclosed herein, the mammal or subject is a human. In some embodiments, compounds provided herein are administered to humans. In some embodiments, compounds provided herein are administered orally. In some embodiments, described herein is a method of treating or preventing a metabolic disorder in an individual, the method comprising: administering to the gastrointestinal tract of the individual a therapeutically effective amount of one or more of the compounds described herein, or a medicament thereof A pharmaceutically acceptable salt or solvate, thereby activating the farnesoid X receptor (FXR) in the intestine, and treating or preventing a metabolic disorder in a subject. In some embodiments, the absorption of the compound is preferentially limited to the intestine. In some embodiments, the method substantially enhances FXR target gene expression in the gut without substantially enhancing FXR target gene expression in the liver or kidney. In some embodiments, the method substantially enhances FXR target gene expression in the gut while minimizing systemic plasma levels of the delivered compound. In some embodiments, the method substantially enhances FXR target gene expression in the gut and liver while minimizing systemic plasma levels of the delivered compound. In some embodiments, the method substantially enhances FXR target gene expression in the gut without substantially enhancing FXR target gene expression in the liver or kidney, while minimizing systemic plasma levels. In some embodiments, the method substantially enhances FXR target gene expression in the gut and liver and provides sustained systemic plasma levels of the delivered compound. In some embodiments, the method reduces or prevents diet-induced weight gain. In some embodiments, the method increases metabolic rate in the individual. In some embodiments, increasing metabolic rate comprises enhancing oxidative phosphorylation in the individual. In some embodiments, the method further comprises improving glucose and/or lipid homeostasis in the individual. In some embodiments, the method does not result in substantial changes in food intake and/or fat consumption in the individual. In some embodiments, the method does not result in a substantial change in appetite in the individual. In some embodiments, the metabolic disorder is selected from obesity, diabetes, insulin resistance, dyslipidemia, or any combination thereof. In some embodiments, the metabolic disorder is non-insulin dependent diabetes. In some embodiments, the method protects against diet-induced weight gain, reduces inflammation, enhances thermogenesis, enhances insulin sensitivity in the liver, reduces hepatic steatosis, promotes BAT activation, reduces blood sugar, increases weight loss, or any combination. In some embodiments, the method enhances insulin sensitivity in the liver and promotes brown adipose tissue (BAT) activation. In some embodiments, the method further comprises administering to the individual an insulin-sensitizing drug, an insulin secretagogue, an alpha-glucosidase inhibitor, a glucagon-like peptide (GLP) agonist, a dipeptidyl peptidase- 4 (DPP-4) inhibitors, nicotinamide nucleosides, analogs of nicotinamide nucleosides, or combinations thereof. In some embodiments, described herein is a method of treating or preventing inflammation in a region of the gut of a subject, the method comprising: administering to the gastrointestinal tract of a subject a therapeutically effective amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby activating the FXR receptor in the intestine, and thereby treating or preventing inflammation in the intestinal region of the individual. In some embodiments, the absorption of the compound is preferentially limited to the intestine. In some embodiments, the method substantially enhances FXR target gene expression in the gut without substantially enhancing FXR target gene expression in the liver or kidney. In some embodiments, inflammation is associated with a clinical condition selected from the group consisting of necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel disorder, gastroenteritis, radiation Induced enteritis, pseudomembranous colitis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, postoperative inflammation, gastric cancer or any combination thereof. In some embodiments, the one or more FXR target genes comprise IBABP, OSTα, Perl, FGF15, FGF19, SHP, or combinations thereof. In some embodiments, the method further comprises administering to the individual a therapeutically effective amount of antibiotic therapy, wherein the method treats or prevents inflammation associated with pseudomembranous colitis in the individual. In some embodiments, the method further comprises administering to the individual a therapeutically effective amount of an oral corticosteroid, other anti-inflammatory or immunomodulatory therapy, nicotinamide, an analog of nicotinamide, or a combination thereof. In some embodiments, the method increases HSL phosphorylation and β3-adrenergic receptor expression. In some embodiments, following administration of the compound, the serum concentration of the compound in the individual remains below its EC50 . In some embodiments, described herein is a method of treating or preventing a cell proliferative disorder in an individual, the method comprising administering to the gastrointestinal tract of the individual a therapeutically effective amount of one or more of the compounds described herein, or a medicament thereof Pharmaceutically acceptable salts or solvates. In some embodiments, the cell proliferative disorder is adenocarcinoma. In some embodiments, the adenocarcinoma is colon cancer. In some embodiments, treating adenocarcinoma reduces adenocarcinoma size, adenocarcinoma volume, number of adenocarcinomas, cachexia resulting from adenocarcinoma; delays progression of adenocarcinoma; increases survival of an individual, or a combination thereof. In some embodiments, the method further comprises administering to the individual an additional therapeutic compound selected from the group consisting of chemotherapeutics, biologics, radiotherapeutics, or combinations thereof. In some embodiments, described herein is a method of treating or preventing a liver disease or condition in an individual, the method comprising administering to the individual a therapeutically effective amount of one or more of the compounds described herein, or their pharmaceutical acceptable salts or solvates. In some embodiments, the liver disease or condition is alcoholic or non-alcoholic liver disease. In some embodiments, the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD) . In some embodiments, the alcoholic liver disease or condition is fatty liver (steatosis), cirrhosis, or alcoholic hepatitis. In some embodiments, the nonalcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD). In some embodiments, the nonalcoholic liver disease or condition is intrahepatic cholestasis or extrahepatic cholestasis. An article of manufacture is provided comprising an encapsulating material; a compound described herein, or a pharmaceutically acceptable salt thereof, in the encapsulating material; and a label indicating the compound or composition, or a pharmaceutically acceptable salt thereof, a pharmaceutically active metabolite The drug, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate is used to treat, prevent or ameliorate one or more symptoms of a disease or condition that would benefit from FXR agonism. Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following embodiments. It should be understood, however, that the embodiments and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from such embodiments. obvious.

交叉引用 本申請案主張2017年3月15日申請的美國臨時專利申請案第62/471,517號之權益，其以全文引用之方式併入本文中。核激素受體，法尼醇X受體(亦稱為FXR或核受體第1子族，第H組，第4成員(NR1H4)) (OMIM：603826)充當膽汁酸代謝之調節因子。FXR為不同組織中之所表現的配位體激活轉錄受體，該等組織包括腎上腺、腎臟、胃、十二指腸、空腸、迴腸、結腸、膽囊、肝臟、巨噬細胞以及白色及棕色脂肪組織。FXR高度表現於參與膽汁酸代謝之組織，諸如肝臟、腸及腎臟中。膽汁酸充當FXR之內源性配位體，以使得膽汁酸之腸溶及全身性釋放在基因表現網路中引起FXR導向之變化。膽汁酸為膽固醇之主要氧化產物，且在一些情況下，在分泌於腸中後，為膽固醇吸收之調節因子。膽固醇轉化成膽汁酸之限速步驟係藉由細胞色素p450酶，膽固醇7-α-羥化酶(CYP7A1)催化且在肝臟中進行。細胞色素p450酶，固醇12-α-羥化酶(CYP8B1)介導膽酸產生且測定兩種主要膽汁酸，膽酸與鵝脫氧膽酸之相對量。FXR之活化可藉由提高肝小雜二聚體搭配物(SHP) (亦稱為核受體第0子族，第B組，第2成員；或NR0B2)之表現水準及小鼠中之纖維母細胞生長因子15 (FGF15)及人類中之纖維母細胞生長因子19 (FGF19)之腸道表現來抑制CYP7A1及CYP8B1之轉錄。SHP抑制肝受體同系物(LRH-1)及肝細胞核因子4α (HNFa4)，其為調節CYP7A1及CYP8B1基因表現之轉錄因子。藉由FXR抑制CYP8B1可為物種特異性的，且FXR活化在一些情況下可在人類中增加CYP8B1表現(Sanyal等人PNAS ,2007 , 104, 15665)。在一些情況下，由腸釋放之FGF15/19隨後活化肝臟中之纖維母細胞生長因子受體4，使得抑制CYP7A1及CYP8B1之有絲分裂原活化蛋白激酶(MAPK)信號傳導路徑激活。 在一些實施例中，較高水準之膽汁酸與胰島素抗性相關聯。舉例而言，胰島素抗性有時會導致自血液吸收的葡萄糖降低且增加肝臟中之新生葡萄糖產量。在一些情況下，膽汁酸之腸道螯合作用已顯示會藉由促進自腸道L細胞分泌類升糖素肽-1 (GLP1)來改良胰島素抗性。GLP-1為源自升糖素原基因之轉錄產物的腸促胰液素。其響應於食物攝入而釋放且對食慾及胃腸道功能施加控制且促進由胰臟分泌胰島素。GLP-1之生物活性形式包括GLP-1-(7-37)及GLP-1-(7-36)NH2 ，其由升糖素原分子之選擇性裂解而產生。在此類情況下，活化FXR使得與降低胰島素抗性相關的膽汁酸之產量降低。 在一些實施例中，活化FXR亦與胰臟多肽摺疊，諸如肽YY (PYY或PYY3-36)之分泌相關。在一些情況下，肽YY為調節下丘腦及腦幹中之神經元活動的腸道激素肽，該下丘腦及腦幹為與獎賞處理(reward processing)有關的大腦區域。在一些情況下，降低之PYY水準與增加之食慾及體重增加相關。 在一些情況下，活化FXR會間接引起血漿三酸甘油酯降低。血流中三酸甘油酯之清除係歸因於脂蛋白脂肪酶(LPL)。LPL活性係藉由誘導其活化因子脂蛋白元CII來增強，且抑制肝臟中的其抑制因子脂蛋白元CIII發生在活化FXR後。 在一些情況下，活化FXR會進一步調節能量消耗，諸如脂肪細胞分化及功能。脂肪組織包含脂肪細胞(adipocyte/fat cell)。在一些情況下，脂肪細胞進一步分化成棕色脂肪組織(BAT)或白色脂肪組織(WAT)。BAT之功能在於產生體熱，而WAT充當脂肪儲存組織。 在一些情況下，FXR普遍表現於腸中。在一些情況下，活化FXR已顯示會誘導腸中FGF19(或小鼠中之FGF15)之表現及分泌。FGF19為調節膽汁酸合成之激素且會對葡萄糖代謝、脂質代謝及能量消耗施加影響。在一些情況下，亦觀測到FGF19會調節脂肪細胞功能及分化。實際上，有研究已顯示，向餵養高脂飲食之小鼠投與FGF19會增加能量消耗、調節脂肪細胞分化及功能、逆轉體重增加且改良胰島素抗性(參見，Fu等人, 「纖維母細胞生長因子19會增加代謝速率且逆轉膳食及瘦素缺乏性糖尿病」。Endocrinology 145 :2594-2603 (2004))。 在一些情況下，腸道FXR活性亦顯示與降低微生物群落之過度生長有關，諸如在餵養期間(Li等人, Nat Commun 4:2384, 2013)。舉例而言，有研究顯示，活化FXR與迴腸中的數種基因，諸如Ang2 、 iNos 及Il18 增加之表現相關，該等基因具有已獲確認之抗微生物作用。(Inagaki等人, Proc Natl Acad Sci U S A 103:3920-3925, 2006)。 在一些情況下，已表明FXR在腸中之阻擋功能及免疫調節作用。FXR調節與肝臟及腸中之膽汁鹽合成、輸送及代謝有關的基因之轉錄，且在一些情況下，顯示引起腸道炎症改良且預防腸道中之細菌位移(Gadaleta等人,Gut. 2011 Apr; 60(4):463-72 )。 在一些情況下，膽汁酸之過度產生或膽汁酸之不當輸送及再循環可導致腹瀉。FXR調節與肝臟及腸中之膽汁鹽合成、輸送及代謝有關的基因之轉錄，且在一些情況下，可能會引起腹瀉改良 Camilleri,Gut Liver. 2015 May; 9(3): 332-339 。 G蛋白偶聯膽汁酸受體1 (亦稱為GPBAR2、GPCR19、膽汁酸或膜型受體或M-BAR或TGR5)為膽汁酸之細胞表面受體。用膽汁酸活化後，TGR5引起產生胞內cAMP，其隨後由於活化BAT中之脫碘酶(DIO2)而觸發三碘甲狀腺素增加，引起增加之能量消耗。 因此，在一些實施例中，代謝過程之調節，諸如膽汁酸合成、膽汁酸循環、葡萄糖代謝、脂質代謝或胰島素敏感度係藉由活化FXR來調節。此外，在一些實施例中，代謝過程之調節異常，諸如膽汁酸合成、膽汁酸循環、葡萄糖代謝、脂質代謝或胰島素敏感度會引起代謝疾病，諸如糖尿病或糖尿病相關病狀或病症、酒精性或非酒精性肝臟疾病或病狀、腸道炎症或細胞增殖性病症。 在某些實施例中，本文揭示作為FXR促效劑的具有活性之化合物。在一些實施例中，本文所述之FXR促效劑在結構上不同於膽汁酸、其他合成性FXR配位體及其他天然FXR配位體。 在一些實施例中，本文亦揭示藉由投與治療有效量之FXR促效劑來治療或預防代謝障礙，諸如糖尿病、肥胖、葡萄糖耐受性異常、血脂異常或胰島素抗性之方法。在一些情況下，向個體之胃腸道投與化合物。 在其他實施例中，本文揭示用於藉由向有需要之個體投與治療有效量之FXR促效劑(例如經由胃腸道)來治療或預防酒精性或非酒精性肝臟疾病或病狀(例如膽汁鬱積、原發性膽汁性肝硬化症、脂肪變性、肝硬化症、酒精性肝炎、非酒精性脂肪變性肝炎(NASH)、非酒精性脂肪肝病(NAFLD)、原發性硬化性膽管炎(PSC)或肝酶升高)之方法。在其他實施例中，本文所揭示之內容包括用於藉由向有需要之個體投與治療有效量之FXR促效劑來治療或預防膽汁鬱積、肝硬化症、原發性膽汁性肝硬化症、非酒精性脂肪變性肝炎(NASH)、非酒精性脂肪肝病(NAFLD)或原發性硬化性膽管炎(PSC)之方法。在一些實施例中，本文所揭示之內容包括用於藉由向有需要之個體投與治療有效量之FXR促效劑來治療或預防膽汁鬱積之方法。在一些實施例中，本文所揭示之內容包括用於藉由向有需要之個體投與治療有效量之FXR促效劑來治療或預防原發性膽汁性肝硬化症之方法。在一些實施例中，本文所揭示之內容包括用於藉由向有需要之個體投與治療有效量之FXR促效劑來治療或預防NASH之方法。在一些實施例中，本文所揭示之內容包括用於藉由向有需要之個體投與治療有效量之FXR促效劑來治療或預防NAFLD之方法。 在其他實施例中，本文所揭示之內容包括用於藉由向有需要之個體投與治療有效量之FXR促效劑(例如經由胃腸道)來治療或預防腸中之炎症及/或細胞增殖性病症，諸如癌症之方法。 在又其他實施例中，本文所揭示之內容包括調節與代謝過程，諸如膽汁酸合成、葡萄糖代謝、脂質代謝或胰島素敏感度相關聯的蛋白質或基因中之一或多者，諸如增加FGF19 (小鼠中之FGF15)之活性、增加GLP-1之分泌或增加PYY之分泌的FXR促效劑。代謝病症 在某些實施例中，本文揭示治療有需要之個體中的代謝障礙之方法。本文所述之內容亦包括預防有需要之個體中的代謝障礙之方法。在一些情況下，此等方法包括向有需要之個體投與治療有效量的本文所揭示之化合物中之一或多者。在一些情況下，一或多種本文所揭示之化合物吸收於胃腸(GI)道中。在其他情況下，吸收於胃腸道中的一或多種所揭示之化合物會活化FXR受體，由此治療或預防個體中之代謝障礙。 在一些實施例中，所揭示之化合物展現全身暴露。在一些情況下，所揭示之化合物在腸中局部暴露，但限制性地暴露於肝臟中或限制性地全身性地暴露。在一些實施例中，所揭示之化合物在腸中之局部暴露可藉由調節腸中之FXR靶基因來展現。在一些實施例中，靶基因可包括：SHP、FGF19 (FGF15)、IBABP、C3、OST α/β。在一些實施例中，所揭示之化合物在腸中暴露約40%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、99%、99.5 %或高於99.5 %。在一些情況下，所揭示之化合物在全身循環中暴露約0.5%、1%、5%、10%、15%、20%、25%、30%、40%、50%或小於50%。在一些實施例中，FXR促效劑在腸腔中之暴露會降低由系統性作用產生之副作用的機率，由此改良療法之安全概況。在其他實施例中，所揭示之化合物會增強腸中之FXR靶基因表現。在其他實施例中，所揭示之化合物進一步調節FXR介導之路徑中的基因表現，諸如抑制肝臟中之CYP7A1及CYP8B1基因表現的FGF19 (FGF15)。在一些情況下，所揭示之化合物增強FXR介導之途徑中的基因表現。在其他情況下，所揭示之化合物降低或抑制FXR介導之途徑中的基因表現。在一些情況下，相對於不存在所揭示之化合物下的基因表現，腸、肝臟、腎臟或其他組織中之基因表現增強約1%、5%、10%、15%、20%、25%、30%、40%、50%、60%、70%、80%、90%、100%、200%、300%、500%、1,000%、5,000%、10,000%、50,000%、100,000%、500,000%或高於500,000%。在一些情況下，相對於不存在所揭示之化合物下的基因表現，腸、肝臟、腎臟或其他組織中之基因表現降低約100%、90%、80%、70%、60%、50%、40%、30%、25%、20%、15%、10%、5%、1%或小於1%。 在一些實施例中，該方法實質上增強腸中之FXR靶基因表現，同時將所遞送化合物之全身血漿水準降至最低。在一些實施例中，該方法實質上增強腸及肝臟中之FXR靶基因表現，同時將所遞送化合物之全身血漿水準降至最低。在一些實施例中，該方法實質上增強腸中之FXR靶基因表現，同時並不會實質上增強肝臟或腎臟中之FXR靶基因表現，且同時將全身血漿水準降至最低。在一些實施例中，該方法實質上增強腸及肝臟中之FXR靶基因表現，且提供所遞送化合物之持續全身血漿水準。 在一些實施例中，代謝障礙係指涉及碳水化合物、脂質、蛋白質、核酸或其組合之正常代謝發生改變的任何病症。在一些情況下，代謝障礙與代謝路徑中之缺乏或過量相關聯，其導致核酸、蛋白質、脂質及/或碳水化合物之代謝失衡。影響代謝之因子包括(但不限於)內分泌(激素)控制系統(例如胰島素路徑、包括GLP-1、調酸素、PYY或其類似者之腸內分泌激素)或神經控制系統(例如大腦中之GLP-1)。例示性代謝障礙包括(但不限於)糖尿病、胰島素抗性、血脂異常、肝病、炎症相關腸道病狀、細胞增殖性病症或其類似者。糖尿病及糖尿病相關病狀或病症 在一些實施例中，本文揭示利用投與本文所述之FXR促效劑來治療患有糖尿病或糖尿病相關病狀或病症之個體的方法。在一些情況下，糖尿病係II型糖尿病或非胰島素依賴型糖尿病(NIDDM)。在一些情況下，糖尿病相關病狀或病症包括肥胖、葡萄糖耐受性異常、血脂異常及胰島素抗性。在一些情況下，糖尿病相關病狀或病症進一步包括二級併發症，諸如動脈粥樣硬化、中風、脂肪肝病、失明、膽囊疾病或多囊性卵巢病。在一些情況下，投與FXR促效劑來治療II型糖尿病、肥胖、葡萄糖耐受性異常、血脂異常、胰島素抗性或二級併發症，諸如動脈粥樣硬化、中風、脂肪肝病、失明、膽囊疾病或多囊性卵巢病。 在一些實施例中，糖尿病個體(例如II型糖尿病個體)之特徵進一步在於身體質量指數(BMI)為25或大於25、30或大於30、35或大於35、40或大於40，諸如BMI為25至29、30至34或35至40。 在一些實例中，本文所述之FXR促效劑降低或預防個體體重增加。在一些情況下，體重增加為飲食誘發之體重增加。在其他情況下，體重增加為非飲食相關的，諸如家族性/遺傳性肥胖或由藥物引起之肥胖。在一些實例中，此類方法降低或預防個體體重增加至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，降低或預防體重增加約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，體重增加之降低或預防係相對於未經FXR促效劑治療之個體中所觀測到的體重增加之降低或預防。 類似地，在一些情況下，FXR促效劑降低個體之BMI。在一些實例中，相對於未經FXR促效劑治療之個體，此類方法將個體之BMI降低至少5%、至少10%、至少15%、至少20%、至少25%、至少30%或更多。在一些情況下，個體為超重的而非肥胖。在其他情況下，個體既不超重亦不肥胖。 在一些情況下，投與FXR促效劑引起血清脂質之量降低。在一些實例中，血清脂質之量降低至少5%、至少10%、至少15%、至少20%、至少30%、至少50%、至少60%、至少70%、至少75%或更多。在一些情況下，血清脂質之量降低約5%至約50%、約5%至約25%、約10%至約20%、約10%至約70%或約10%至約30%。在一些情況下，血清脂質之量的降低係相對於未經FXR促效劑治療之個體中所觀測到的血清脂質之量。 在一些實例中，投與FXR促效劑引起三酸甘油酯(例如肝三酸甘油酯)水準降低。在一些情況下，三酸甘油酯(例如肝三酸甘油酯)水準降低至少5%、至少10%、至少15%、至少20%、至少30%、至少50%、至少60%、至少70%、至少75%或更多。在一些情況下，三酸甘油酯(例如肝三酸甘油酯)水準降低約5%至約50%、約5%至約25%、約10%至約20%、約10%至約70%或約10%至約30%。在一些情況下，三酸甘油酯(例如肝三酸甘油酯)水準之降低係相對於未經FXR促效劑治療之個體中所觀測到的三酸甘油酯(例如肝三酸甘油酯)水準。 在一些實例中，投與FXR促效劑引起對肝臟中之胰島素的胰島素敏感度增加。在一些情況下，胰島素敏感度增加至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，胰島素敏感度增加約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，胰島素敏感度之增加係相對於未經FXR促效劑治療之個體中所觀測到的敏感度。 在一些實施例中，投與FXR促效劑引起個體中的血清胰島素之量降低。在一些實例中，血清胰島素降低至少5%、至少10%、至少15%、至少20%、至少30%、至少50%、至少60%、至少70%、至少75%或更多。在一些情況下，血清胰島素降低約5%至約50%、約5%至約25%、約10%至約20%、約10%至約70%或約10%至約30%。在一些情況下，血清胰島素水準之降低係相對於未經FXR促效劑治療之個體中所觀測到的水準。 在一些實施例中，投與FXR促效劑引起個體中的血清葡萄糖之量降低。在一些實例中，血清葡萄糖降低至少5%、至少10%、至少15%、至少20%、至少30%、至少50%、至少60%、至少70%、至少75%或更多。在一些情況下，血清葡萄糖降低約5%至約50%、約5%至約25%、約10%至約20%、約10%至約70%或約10%至約30%。在一些情況下，血清葡萄糖水準之降低係相對於未經FXR促效劑治療之個體中所觀測到的水準。 在一些實例中，本文所述之FXR促效劑增加個體中白色脂肪組織變棕色。在一些實例中，相對於未經FXR促效劑治療之個體，個體中白色脂肪組織變棕率增加至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。 在一些實施例中，投與FXR促效劑並未引起個體中之攝食量及/或脂肪消耗量發生實質變化。在一些情況下，攝食量及/或脂肪消耗量降低諸如小於15%、小於10%或小於5%。在一些實施例中，個體中之食慾未發生實質變化。在其他實施例中，報導出個體食慾下降為極小的。 在一些實施例中，投與FXR促效劑引起個體中之代謝速率增加。在一些情況下，FXR促效劑增加個體中之代謝速率。在一些情況下，個體中之代謝速率增加至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少75%或更多。在一些情況下，代謝速率增加約5%至約50%、約5%至約25%、約10%至約20%、約10%至約70%或約10%至約30%。在一些情況下，代謝速率之增加係相對於未經FXR促效劑治療之個體中所觀測到的速率。 在一些實施例中，代謝增加係由個體中增強之氧化磷酸化引起，其隨後引起組織(諸如BAT)能量消耗增加。在此等情況下，FXR促效劑有助於增加BAT活性。在一些實例中，BAT活性增加至少5%、至少10%、至少15%、至少20%、至少30%、至少50%、至少60%、至少70%、至少75%或更多。在一些情況下，BAT活性增加約5%至約50%、約5%至約25%、約10%至約20%、約10%至約70%或約10%至約30%。在一些情況下，BAT活性係相對於未經FXR促效劑治療之個體中所觀測到的BAT活性。酒精性及非酒精性肝臟疾病或病狀 本文所揭示之內容包括預防及/或治療酒精性或非酒精性肝臟疾病或病狀。例示性酒精性或非酒精性肝臟疾病或病狀包括(但不限於)膽汁鬱積、肝硬化症、脂肪變性、酒精性肝炎、非酒精性脂肪變性肝炎(NASH)、非酒精性脂肪肝病(NAFLD)、原發性硬化性膽管炎(PSC)、肝酶升高及三酸甘油酯水準升高。在一些實施例中，FXR促效劑用於預防或治療酒精性或非酒精性肝臟疾病。在一些實施例中，FXR促效劑用於預防或治療膽汁鬱積、肝硬化症、脂肪變性、酒精性肝炎、非酒精性脂肪變性肝炎(NASH)、非酒精性脂肪肝病(NAFLD)或原發性硬化性膽管炎(PSC)。膽汁鬱積 在一些實施例中，本文所揭示之FXR促效劑用於治療個體中之膽汁鬱積。膽汁鬱積，膽汁流動減弱或停止，其在一些情況下會由於膽汁酸及肝臟中之其他毒素的堆積而導致肝毒性。在一些情況下，膽汁鬱積為多種肝臟疾病之一組成部分，該等肝臟疾病包括膽汁鬱積、妊娠期膽汁鬱積、原發性膽汁性肝硬化症(PBC)及原發性硬化性膽管炎(PSC)。在一些情況下，阻塞係歸因於膽結石、膽創傷、藥物、一或多種其他肝臟疾病或癌症。在一些情況下，膽汁酸之腸肝循環使得能夠自腸吸收脂肪及脂溶性維生素且允許自肝臟消除膽固醇、毒素及代謝副產物，諸如膽紅素。在一些情況下，FXR之活化誘導微管膽汁轉運體BSEP (ABCB11)及多藥抗性相關蛋白2 (MRP2；ABCC2、cMOAT)之表現，且抑制與膽汁酸生物合成有關之基因，諸如固醇12α-羥化酶(CYP8B1)及CYP7A1。 在一些實例中，FXR促效劑使個體中之膽汁鬱積減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，膽汁鬱積減少約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，膽汁鬱積之水準係相對於未經FXR促效劑治療之個體中的膽汁鬱積之水準。原發性膽汁性肝硬化症及肝硬化 在一些實施例中，本文所揭示之FXR促效劑用於治療個體中之原發性膽汁性肝硬化症(PBC)。PBC為主要由將膽汁酸(BA)輸送至肝臟外之膽管的自體免疫損壞造成的肝病，其導致膽汁鬱積。伴隨PBC發展，BA之持續性毒性堆積會引起進行性肝臟損傷。慢性炎症及纖維化可發展為肝硬化症。在一些實例中，FXR促效劑使個體中之PBC減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，PBC減少約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，PBC之水準係相對於未經FXR促效劑治療之個體中的PBC之水準。 在一些實施例中，本文所揭示之FXR促效劑會減少個體中之肝硬化症。在一些實例中，FXR促效劑使個體中之肝硬化症減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，肝硬化症減少約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，肝硬化症之水準係相對於未經FXR促效劑治療之個體中的肝硬化症之水準。非酒精性脂肪肝病及非酒精性脂肪變性肝炎 非酒精性脂肪肝病(NAFLD)與肝臟中之過量脂肪(脂肪變性)相關聯，且在一些情況下，會發展為NASH，其由炎症、細胞死亡及纖維化之組織學標誌界定。在一些情況下，原發性NASH與胰島素抗性相關聯，而繼發性NASH係由醫學或外科病狀或藥物，諸如(但不限於)他莫昔芬(tamoxifen)所引起。在一些情況下，NASH會發展為晚期纖維化、肝細胞癌或需要肝臟移植之末期肝病。 在一些情況下，NASH係由於三酸甘油酯(TG)不平衡而產生。舉例而言，功能異常脂肪細胞會分泌促炎性分子，諸如細胞介素及趨化激素，引起胰島素抗性及脂肪細胞中脂肪分解抑制失效。在一些情況下，此脂肪分解抑制失效會導致游離脂肪酸(FFA)釋放至肝臟中之循環及攝取中。在一些情況下，呈三酸甘油酯(TG)形式之FFA在脂滴中之過度積聚會導致氧化應激、線粒體功能異常及促炎性分子上調。 在一些情況下，活化FXR會抑制三酸甘油酯(TG)/脂肪酸(FA)合成，該合成係藉由經由活化SHP抑制固醇調節元件-結合蛋白1c (SREBP1c)來推進。在一些情況下，FXR會另外藉由刺激脂蛋白脂肪酶(LPL)活性增加TG清除率，且藉由誘導多配體蛋白聚糖1 (SDC1)及VLDL受體(VLDLR)增加殘餘物及低密度脂蛋白之肝攝取。 在一些實施例中，本文所揭示之FXR促效劑用於治療非酒精性脂肪變性肝炎(NASH)。在一些實例中，FXR促效劑使個體中之NASH減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，NASH減少約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，NASH之水準係相對於未經FXR促效劑治療之個體中的NASH之水準。 在一些實施例中，本文所揭示之FXR促效劑用於治療NAFLD。在一些實例中，FXR促效劑使個體中之NAFLD減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，NAFLD減少約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，NAFLD之水準係相對於未經FXR促效劑治療之個體中的NAFLD之水準。脂肪變性 在一些實施例中，本文所揭示之FXR促效劑減少個體中之脂肪肝(脂肪變性)。在一些實例中，FXR促效劑使個體中之脂肪變性減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，脂肪變性減少約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，脂肪變性之水準係相對於未經FXR促效劑治療之個體中的脂肪變性之水準。膨大 肝細胞膨大表示細胞損傷之特徵，為NASH之一特徵。膨大為表示進行性NAFL (3型及4型)之特徵。該術語適用於增大、出現腫脹之肝細胞；受影響細胞通常互混於脂肪變性區域處及典型脂肪變性肝炎、血管周區域處。肝細胞膨大最常見於可H & E偵測之竇狀隙周圍纖維化。當其含有MH(典型的或以不佳形式形成的)時，膨大肝細胞最易於見到。肝細胞膨大為微管中斷及嚴重細胞損傷之結構性表現。 在一些實施例中，本文所揭示之FXR促效劑減少個體中之肝臟膨大。在一些實例中，FXR促效劑使個體中之肝臟膨大減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，肝臟膨大減少約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，肝臟膨大係相對於未經FXR促效劑治療之個體中的肝臟膨大之水準。酒精性肝炎 在一些實施例中，本文所揭示之FXR促效劑會減少個體中之酒精性肝炎。在一些實例中，FXR促效劑使個體中之酒精性肝炎減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，酒精性肝炎之水準降低約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，酒精性肝炎之水準係相對於未經FXR促效劑治療之個體中的酒精性肝炎之水準。原發性硬化性膽管炎 在一些實施例中，本文所揭示之FXR促效劑用於治療原發性硬化性膽管炎(PSC)。PSC為慢性及進行性膽汁鬱積性肝病。PSC之特徵在於進行性炎症、纖維化及肝管狹窄形成。常見症狀包括搔癢及黃疸。疾病在很大程度上與發炎性腸病(IBD)相關聯——約5%之患有潰瘍性結腸炎之患者將患有PSC。高達70%的患有PSC之患者亦患有IBD，最常見為潰瘍性結腸炎。其他酒精性及非酒精性肝臟疾病或病狀 在一些實施例中，本文所揭示之FXR促效劑減少個體中之肝酶。在一些實例中，FXR促效劑使個體中之肝酶(例如血清ALT及/或AST水準)減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，肝酶水準下降約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，肝酶水準係相對於未經FXR促效劑治療之個體中的肝酶水準。 在一些實施例中，本文所揭示之FXR促效劑減少個體中之肝三酸甘油酯。在一些實例中，FXR促效劑使個體中之肝三酸甘油酯減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，肝三酸甘油酯之水準降低約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，肝三酸甘油酯水準係相對於未經FXR促效劑治療之個體中的肝三酸甘油酯水準。發炎性腸道病狀 本文揭示治療或預防發炎性腸道病狀之方法。例示性發炎性病狀包括壞死性小腸結腸炎(NEC)、胃炎、潰瘍性結腸炎、發炎性腸病、大腸急躁症、偽膜性結腸炎、胃腸炎、輻射誘發腸炎、化學療法誘發腸炎、胃-食道逆流病(GERD)、消化性潰瘍、非潰瘍性消化不良(NUD)、乳糜瀉、腸道乳糜瀉、減肥手術(bariatric surgery)之後的胃腸道併發症、胃癌發生或胃或腸道切除之後的胃癌發生。在一些實施例中，發炎性病狀為NEC且個體為新生兒或早產嬰兒。在一些實施例中，個體為經腸餵養之嬰兒或經配方乳品餵養之嬰兒。 在一些實施例中，向患有發炎性腸道病狀之個體投與本文所揭示之FXR促效劑。在一些實施例中，向患有以下之個體投與本文所揭示之FXR促效劑：壞死性小腸結腸炎(NEC)、胃炎、潰瘍性結腸炎、發炎性腸病、大腸急躁症、偽膜性結腸炎、胃腸炎、輻射誘發腸炎、化學療法誘發腸炎、胃-食道逆流病(GERD)、消化性潰瘍、非潰瘍性消化不良(NUD)、乳糜瀉、腸道乳糜瀉、減肥手術之後的胃腸道併發症、胃癌發生或胃或腸道切除之後的胃癌發生。 在一些實施例中，本文所揭示之FXR促效劑降低個體(諸如人類)中之腸的炎症。在一些實例中，FXR促效劑使個體中之腸道炎症降低至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，腸道炎症降低約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，腸道炎症之水準係相對於未經FXR促效劑治療之個體中的腸道炎症之水準。胃腸道疾病 在某些實施例中，本文揭示治療或預防有需要之個體中的胃腸道疾病之方法，該等方法包含向個體投與如本文所述之法尼醇X受體(FXR)促效劑。在一些實施例中，胃腸道疾病為大腸急躁症(IBS)、伴隨腹瀉之大腸急躁症(IBS-D)、伴隨便秘之大腸急躁症(IBS-C)、混合型IBS (IBS-M)、未定型IBS (IBS-U)或膽汁酸腹瀉(BAD)。 大腸急躁症 大腸急躁症(IBS)為持續超過較長時段，通常數年的包括腹痛之症狀與排便型樣變化的組合。IBS之病因仍不明確；然而認為腸動力問題、食物敏感性、遺傳因子、小腸細菌過度生長及腸-腦軸線問題具有潛在作用。在一些情況下，伴有腹瀉之IBS歸類為伴隨腹瀉之IBS (IBS-D)。在一些情況下，伴有便秘之IBS歸類為伴隨便秘之IBS (IBS-C)。在一些情況下，伴有腹瀉與便秘之交替型樣的IBS歸類為混合型IBS (IBS-M)。在一些情況下，IBS未伴有腹瀉或便秘任一者且歸類為未定型IBS (IBS-U)。在一些情況下，IBS具有四種不同變化形式：IBS-D、IBS-C、IBS-M及IBS-U。 在一些實施例中，由不同病狀模擬IBS之症狀。在一些實施例中，糖消化不良、乳糜瀉、未伴隨乳糜瀉之麩質不耐症、胰臟外分泌不足、小腸細菌過度生長、顯微性結腸炎或膽汁酸吸收障礙(BAM)模擬IBS-D。在一些實施例中，盆底失弛緩(anismus)、盆底共濟不能(pelvic floor dyssynergia)或恥骨直腸肌痙攣(puborectalis spasm)或會陰下降症候群模擬IBS-C。 在一些實施例中，本文所揭示之FXR促效劑用於治療哺乳動物中之IBS或其變化形式中之任一者。在一些實例中，FXR促效劑治療劑使哺乳動物中之IBS症狀減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。 膽汁酸吸收障礙 膽汁酸吸收障礙(BAM)，亦稱為膽汁酸腹瀉(BAD)、膽汁酸誘發腹瀉、膽汁溢出性腸病(cholerheic enteropathy)或激膽性腸病(choleretic enteropathy)或膽汁鹽吸收障礙，其為其中結腸中膽汁酸之存在會引起腹瀉之病狀。BAM係由多種條件引起，諸如克羅恩氏病、膽囊切除術、腹腔病、放射線療法及胰臟病。在一些情況下，BAM係由藥物，諸如二甲雙胍引起。在一些實施例中，BAM係由膽汁酸之過度產生引起。膽汁酸合成經迴腸激素纖維母細胞生長因子19 (FGF-19)受到不利調節；低水準之FGF-19導致膽汁酸增加。FXR活化促進FGF-19之合成，由此降低膽汁酸水準。 在一些實施例中，本文所揭示之FXR促效劑用於治療哺乳動物中之BAM。在一些實施例中，本文所揭示之FXR促效劑減少膽汁酸合成。在一些實施例中，本文所揭示之FXR促效劑降低膽汁酸水準。在一些實施例中，FXR促效劑及本文所揭示之另一種治療劑預防BAD。在一些實例中，FXR促效劑使哺乳動物中之BAM症狀減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。移植物抗宿主疾病 (GvHD) 移植物抗宿主疾病(GvHD)為自組織不相容供體(亦即遺傳學或免疫學上不同的供體)移植組織或細胞之後產生的醫學併發症。供給組織或細胞(移植物)中之免疫細胞將接受者(宿主)認定為外來的且會發起攻擊。引起GvHD的移植組織或細胞之非限制性實例為血液製劑、諸如骨髓細胞之幹細胞及器官。存在不同類型之GvHD，其視顯現或出現症狀所處之位置而定：表皮GvHD、肝GvHD、眼GvHD、神經肌肉GvHD、泌尿生殖道GvHD及胃腸(GI)道GvHD。胃腸道GvHD之症狀包括吞咽困難、吞咽疼痛、體重減輕、噁心、嘔吐、腹瀉及/或腹部痙攣。胃腸道GvHD會引起黏膜脫落及嚴重腸道炎症。膽上皮之炎症適合於藉由核受體，諸如糖皮質激素受體(GR)、FXR或過氧化體增殖物活化受體(PPAR)來控制。在一些實施例中，本文所揭示之FXR促效劑用於治療哺乳動物中之GvHD或GvHD之併發症。在一些實施例中，本文所揭示之FXR促效劑用於治療哺乳動物中之胃腸道GvHD或胃腸道GvHD之併發症。在一些實例中，FXR促效劑使哺乳動物中之胃腸道GvHD或胃腸道GvHD之併發症減少至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，胃腸道GvHD或胃腸道GvHD之併發症減少約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些實施例中，本文所揭示之FXR促效劑減少由胃腸道GvHD所引起之腸道炎症。在一些實施例中，本文所揭示之FXR促效劑使由胃腸道GvHD所引起之腸道炎症減少約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。腎病 在某些實施例中，本文揭示治療或預防有需要之個體中的腎病之方法，該等方法包含向個體投與本文所述之法尼醇X受體(FXR)促效劑。在一些實施例中，腎病與肝病相關聯。在一些實施例中，腎病與纖維化肝病相關聯。在一些實施例中，腎病與代謝肝病相關聯。在一些實施例中，腎病與代謝病狀相關聯，諸如(但不限於)糖尿病、代謝症候群、NAFLD、胰島素抗性、脂肪酸代謝病症及膽汁鬱積。在一些實施例中，腎病為糖尿病性腎病變、與纖維化相關聯腎病、不與纖維化相關聯之腎病、腎纖維化或其任何組合。 糖尿病性腎病變 糖尿病性腎病變為特徵在於以下之腎病：腎臟之腎小球出現損傷。糖尿病促成過量產生反應性氧物質，其導致腎病症候群及腎小球留下疤痕。伴隨糖尿病性腎病變發展，腎小球濾過障壁(GFB)日益受損，且因此，血液中之蛋白質經由該障壁漏泄且積聚於鮑氏空間(Bowman's space)中。 在一些實施例中，本文所揭示之FXR促效劑用於治療哺乳動物中之糖尿病性腎病變。 腎纖維化 腎纖維化之特徵在於纖維母細胞活化且胞外基質或結締組織過量沈積於腎臟中，其為慢性腎病之標誌。FXR在保護避免腎纖維化中起重要作用。FXR之活化會抑制腎纖維化且減少細胞外基質蛋白積聚於腎臟中。 在一些實施例中，本文所揭示之FXR促效劑用於治療哺乳動物中之腎纖維化。 在一個態樣中，本文描述一種治療或預防哺乳動物中之腎臟疾病或病狀的方法，該方法包含向哺乳動物投與本文所揭示之FXR促效劑或其醫藥學上可接受之鹽或溶劑合物。在一些實施例中，腎臟疾病或病狀為糖尿病性腎病變、與纖維化相關聯腎病、不與纖維化相關聯之腎病、腎纖維化、與代謝疾病相關聯之腎病、慢性腎病、多囊性腎病、急性腎病或其任何組合。細胞增殖疾病 本文進一步揭示預防或治療例如特定類型之癌症中的細胞增殖疾病之方法。在一些實施例中，本文所揭示之FXR促效劑用於預防或治療腺癌或衍生自腺組織或其中腫瘤細胞形成可辨識腺結構之癌瘤。在一些實施例中，根據細胞排列之主要型樣將腺癌歸類為乳頭狀、泡狀，或根據細胞之特定產物將其歸類為黏液性腺癌。在一些情況下，例如在結腸、腎臟、乳房、子宮頸、食道、胃、胰臟、前列腺或肺中觀測到腺癌。 在一些實施例中，本文所揭示之化合物用於預防或治療腸癌，諸如結腸癌，例如形成於結腸(大腸之最長部分)組織中的癌症，或腸之另一部分，諸如空腸及/或迴腸之癌症。在一些情況下，結腸癌亦稱作「結腸直腸癌」。在一些情況下，結腸癌之最常見類型為結腸腺癌。 在一些情況下，癌症進展係藉由體內癌症之癌期或程度表徵。分期通常係基於腫瘤尺寸、淋巴結中癌症之存在及除原發癌部位外之部位處的癌症之存在。結腸癌之癌期包括I期、II期、III期及IV期。在一些實施例中，結腸腺癌來自任何癌期。在其他實施例中，結腸腺癌為I期癌症、II期癌症或III期癌症。 在一些實施例中，向患有I期、II期、III期或IV期癌症之個體投與本文所述之FXR促效劑。在一些實施例中，向患有I期、II期或III期結腸腺癌之個體投與本文所述之FXR促效劑。 在一些實施例中，本文所揭示之FXR促效劑進一步降低個體中之腫瘤負荷。在一些實例中，FXR促效劑使個體中之腫瘤負荷(諸如結腸腫瘤負荷)降低至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，腫瘤負荷降低約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，腫瘤負荷之水準係相對於未經FXR促效劑治療之個體中的腫瘤負荷之水準。 在一些情況下，本文所揭示之FXR促效劑進一步減小個體中之腫瘤尺寸及/或體積。在一些情況下，FXR促效劑使個體中之腫瘤(諸如結腸腫瘤)尺寸及/或體積減小至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，腫瘤尺寸減小約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，腫瘤尺寸係相對於未經FXR促效劑治療之個體中的腫瘤尺寸。 在其他實施例中，本文所揭示之FXR促效劑減小個體中因腫瘤所致的惡病質之影響。在一些實例中，FXR促效劑使個體中惡病質(諸如因結腸腫瘤所致)之影響減小至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，惡病質之影響減小約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，惡病質之影響係相對於未經FXR促效劑治療之個體中的惡病質之影響。 在其他實施例中，本文所揭示之FXR促效劑增加患有腫瘤之個體的存活率。在一些情況下，FXR促效劑使個體中患有腫瘤(諸如結腸癌)的個體之存活率增加至少5%、至少10%、至少15%、至少20%、至少30%、至少40%、至少50%或更多。在一些情況下，存活率增加約5%至約50%、約5%至約25%、約10%至約20%或約10%至約30%。在一些情況下，存活率係相對於未經FXR促效劑治療之個體中的存活率。化合物 本文所述之化合物，包括其醫藥學上可接受之鹽、前藥、活性代謝物及醫藥學上可接受之溶劑合物為法尼醇X受體促效劑。 在一個態樣中，本文描述法尼醇X受體促效劑及其用途。在一個態樣中，本文描述具有式(I)結構之化合物或其醫藥學上可接受之鹽或溶劑合物：

Figure 02_image005
式(I) 其中， X1 為CH或N； R1 為H、D、鹵素、-CN、-OH、-SH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-S(C1 -C4 烷基)、-S(=O)(C1 -C4 烷基)、-S(=O)2 (C1 -C4 烷基)、-S(=O)2 N(R15 )2 、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-C(=O)N(R15 )2 、-NR15 C(=O)(C1 -C4 烷基)、-NR15 C(=O)O(C1 -C4 烷基)、-OC(=O)N(R15 )2 、-NR15 C(=O)N(R15 )2 、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基、C1 -C4 雜烷基或經取代或未經取代之單環C2 -C5 雜環烷基； X2 為CR2 或N； R2 為H、D、鹵素、-CN、-OH、-SH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-S(C1 -C4 烷基)、-S(=O)(C1 -C4 烷基)、-S(=O)2 (C1 -C4 烷基)、-S(=O)2 N(R15 )2 、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-C(=O)N(R15 )2 、-NR15 C(=O)(C1 -C4 烷基)、-NR15 C(=O)O(C1 -C4 烷基)、-OC(=O)N(R15 )2 、-NR15 C(=O)N(R15 )2 、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基或C1 -C4 雜烷基或經取代或未經取代之單環C2 -C5 雜環烷基； 或R1 及R2 與插入原子一起形成經取代或未經取代之5員稠環或經取代或未經取代之6員稠環，在該環中具有0至3個N原子及0至2個O或S原子； X3 為CR3 或N； R3 為H、D、鹵素、-CN、-OH、-SH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-S(C1 -C4 烷基)、-S(=O)(C1 -C4 烷基)、-S(=O)2 (C1 -C4 烷基)、-S(=O)2 N(R15 )2 、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-C(=O)N(R15 )2 、-NR15 C(=O)(C1 -C4 烷基)、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基、C1 -C4 雜烷基或經取代或未經取代之單環C2 -C5 雜環烷基； 各X4 獨立地為CH或N； R4 為H、D、F或-CH3 ； R5 為H、D、F或-CH3 ； 或R4 及R5 一起形成橋鍵，其為-CH2 -或-CH2 CH2 -； 各R6 獨立地為H、D、F、-OH或-CH3 ； m為0、1或2； R7 為H、D、鹵素、-CN、-OH、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基或C1 -C4 雜烷基; L不存在、為-Y2 -L1 -、-L1 -Y2 -、伸環丙基、伸環丁基或雙環[1.1.1]伸戊基； Y2 不存在、為-O-、-S-、-S(=O)-、-S(=O)2 -、-S(=O)2 NR15 -、-CH2 -、-CH=CH-、-C≡C-、-C(=O)-、-C(=O)O-、-OC(=O)-、-OC(=O)O-、-C(=O)NR15 -、-NR15 C(=O)-、-OC(=O)NR15 -、-NR15 C(=O)O-、-NR15 C(=O)NR15 -、-NR15 S(=O)2 -或-NR15 -； L1 不存在或為經取代或未經取代之C1 -C4 伸烷基； X5 為NR8 或N； R8 為H、D、C1 -C6 烷基、C1 -C6 氘代烷基、C1 -C6 氟烷基、C1 -C6 雜烷基、-C(=O)(C1 -C4 烷基)、-CO2 (C1 -C4 烷基)、-C(=O)N(R15 )2 、-S(=O)2 (C1 -C4 烷基)、-S(=O)2 N(R15 )2 、經取代或未經取代之C3 -C6 環烷基或經取代或未經取代之單環C2 -C6 雜環烷基、經取代或未經取代之苯基或經取代或未經取代之單環雜芳基； R9 為H、D、F或-CH3 ； Y為-CR10 R11 -、-O-、-S-、-S(=O)-、-S(=O)2- 或-NR17 -； R10 為H、D、鹵素、-CN、-OH、C1 -C6 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C6 烷氧基、C1 -C6 氟烷基、-SR12 、-S(=O)R14 、-S(=O)2 R14 、或-N(R12 )2 ； R11 為H、D、F或-CH3 ； 或R9 及R11 一起形成橋鍵，其為-CH2 -或-CH2 CH2 -； 各R12 獨立地為H、C1 -C4 烷基、C1 -C4 氘代烷基、C1 -C4 氟烷基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之C2 -C6 雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基、經取代或未經取代之單環雜芳基； R14 為C1 -C4 烷基、C1 -C4 氘代烷基、C1 -C4 氟烷基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之C2 -C6 雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基或經取代或未經取代之單環雜芳基； R15 為H或經取代或未經取代之C1 -C6 烷基； 各R16 獨立地為H、D、鹵素、-CN、-OH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-S(C1 -C4 烷基)、-S(=O)(C1 -C4 烷基)、-S(=O)2 (C1 -C4 烷基)、-C(=O)(C1 -C4 烷基)、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-NR15 C(=O)(C1 -C4 烷基)、-C(=O)N(R15 )2 、-NR15 C(=O)O(C1 -C4 烷基)、-OC(=O)N(R15 )2 、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之單環C2 -C6 雜環烷基、經取代或未經取代之苯基或經取代或未經取代之單環雜芳基； n為0、1或2； R17 為-L5 -R14 ；及 L5 不存在、為-S(=O)2 -、-C(=O)-、-CO2 -或-C(=O)N(R15 )-。 在另一態樣中，本文描述式(I)化合物或其醫藥學上可接受之鹽或溶劑合物：
Figure 02_image007
式(I) 其中， X1 為CH或N； R1 為H、D、鹵素、-CN、-OH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-NR15 C(=O)(C1 -C4 烷基)、-NR15 C(=O)O(C1 -C4 烷基)、-OC(=O)N(R15 )2 、-NR15 C(=O)N(R15 )2 、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基、C1 -C4 雜烷基或經取代或未經取代之單環C2 -C5 雜環烷基； X2 為CR2 或N； R2 為H、D、鹵素、-CN、-OH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-NR15 C(=O)(C1 -C4 烷基)、-NR15 C(=O)O(C1 -C4 烷基)、-OC(=O)N(R15 )2 、-NR15 C(=O)N(R15 )2 、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基或C1 -C4 雜烷基； 或R1 及R2 與插入原子一起形成經取代或未經取代之5員稠環，在該環中具有0至3個N原子及0至2個O或S原子； X3 為CR3 或N； R3 為H、D、鹵素、-CN、-OH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-NR15 C(=O)(C1 -C4 烷基)、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基或C1 -C4 雜烷基； 各X4 獨立地為CH或N； R4 為H、D、F或-CH3 ； R5 為H、D、F或-CH3 ； 或R4 及R5 一起形成橋鍵，其為-CH2 -或-CH2 CH2 -； 各R6 獨立地為H、D、F、-OH或-CH3 ； m為0、1或2； R7 為H、D、鹵素、-CN、-OH、C1 -C4 烷基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基或C1 -C4 雜烷基； L不存在、為-Y2 -L1 -、-L1 -Y2 -、伸環丙基、伸環丁基或雙環[1.1.1]伸戊基； Y2 不存在、為-O-、-S-、-S(=O)-、-S(=O)2 -、-S(=O)2 NR15 -、-CH2 -、-CH=CH-、-C≡C-、-C(=O)-、-C(=O)O-、-OC(=O)-、-OC(=O)O-、-C(=O)NR15 -、-NR15 C(=O)-、-OC(=O)NR15 -、-NR15 C(=O)O-、-NR15 C(=O)NR15 -、-NR15 S(=O)2 -或-NR15 -； L1 不存在或為經取代或未經取代之C1 -C4 伸烷基； X5 為NR8 或N； R8 為H、D、C1 -C6 烷基、C1 -C6 氘代烷基、C1 -C6 氟烷基、C1 -C6 雜烷基、-C(=O)(C1 -C4 烷基)、-CO2 (C1 -C4 烷基)、-C(=O)N(R15 )2 、-S(=O)2 (C1 -C4 烷基)、-S(=O)2 N(R15 )2 、經取代或未經取代之C3 -C6 環烷基或經取代或未經取代之單環C2 -C6 雜環烷基、經取代或未經取代之苯基或經取代或未經取代之單環雜芳基； R9 為H、D或-CH3 ； Y為-CR10 R11 -、-O-、-S-、-S(=O)-、-S(=O)2- 或-NR17 -； R10 為H、D、鹵素、-CN、-OH、C1 -C6 烷基、C1 -C6 烷氧基、C1 -C6 氟烷基、-SR12 、-S(=O)R14 、-S(=O)2 R14 、或-N(R12 )2 ； R11 為H、D或-CH3 ； 或R9 及R11 一起形成橋鍵，其為-CH2 -或-CH2 CH2 -； 各R12 獨立地為H、C1 -C4 烷基、C1 -C4 氘代烷基、C1 -C4 氟烷基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之C2 -C6 雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基、經取代或未經取代之單環雜芳基； R14 為C1 -C4 烷基、C1 -C4 氘代烷基、C1 -C4 氟烷基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之C2 -C6 雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基或經取代或未經取代之單環雜芳基； R15 為H或經取代或未經取代之C1 -C6 烷基； 各R16 獨立地為H、D、鹵素、-CN、-OH、-N(R15 )2 、-NR15 S(=O)2 (C1 -C4 烷基)、-S(C1 -C4 烷基)、-S(=O)2 (C1 -C4 烷基)、-C(=O)(C1 -C4 烷基)、-OC(=O)(C1 -C4 烷基)、-CO2 H、-CO2 (C1 -C4 烷基)、-NR15 C(=O)(C1 -C4 烷基)、-C(=O)N(R15 )2 、-NR15 C(=O)O(C1 -C4 烷基)、-OC(=O)N(R15 )2 、C1 -C4 烷基、C2 -C4 烯基、C2 -C4 炔基、C1 -C4 烷氧基、C1 -C4 氘代烷基、C1 -C4 氘代烷氧基、C1 -C4 氟烷基、C1 -C4 氟烷氧基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之單環C2 -C6 雜環烷基、經取代或未經取代之苯基或經取代或未經取代之單環雜芳基； n為0、1或2； R17 為-L5 -R14 ；及 L5 不存在、為-S(=O)2 -、-C(=O)-、-CO2 -或-C(=O)N(R15 )-。 對於任何及所有實施例而言，取代基係選自所列出之替代物之子集中。舉例而言，在一些實施例中，Y為-CR10 R11 -、-O-、-S-、-S(=O)-、-S(=O)2- 或-NR17 -。在其他實施例中，Y為-CR10 R11 -、-O-或-NR17 -。在一些實施例中，Y為-CR10 R11 -。 在一些實施例中，m為0、1或2。在一些實施例中，m為0或1。在一些實施例中，m為0。在一些實施例中，n為0、1或2。在一些實施例中，n為0或1。在一些實施例中，n為0。 在一些實施例中，L不存在、為-O-、-S-、-CH2 -、-CH2 CH2 -、-CH2 O-、-OCH2 -、-CH2 NR15 -、-NR15 CH2 -、-CH=CH-、-C≡C-、-C(=O)-、-C(=O)O-、-OC(=O)-、-OC(=O)O-、-C(=O)NR15 -、-NR15 C(=O)-、-OC(=O)NR15 -、-NR15 C(=O)O-、-NR15 C(=O)NR15 -、-NR15 S(=O)2 -、-NR15 -、伸環丙基、伸環丁基或雙環[1.1.1]伸戊基。 在一些實施例中，L不存在、為-O-、-S-、-CH2 -、-CH2 CH2 -、-CH2 O-、-OCH2 -、-CH2 NR15 -、-NR15 CH2 -、-CH=CH-、-C≡C-、-C(=O)NR15 -、-NR15 C(=O)-、-OC(=O)NR15 -、-NR15 C(=O)O-、-NR15 C(=O)NR15 -、-NR15 S(=O)2 -、-NR15 -、伸環丙基、伸環丁基或雙環[1.1.1]伸戊基。 在一些實施例中，L不存在或為-C≡C-。 在一些實施例中，R9 為H；R11 為H；或R9 及R11 一起形成橋鍵，其為-CH2 CH2 -。在一些實施例中，R9 為H；且R11 為H。 在一些實施例中，化合物具有式(II)結構，或其醫藥學上可接受之鹽或溶劑合物：
Figure 02_image009
式(II)。 在一些實施例中，L不存在。 在一些實施例中，化合物具有式(III)結構，或其醫藥學上可接受之鹽或溶劑合物：
Figure 02_image011
式(III)。 在一些實施例中，R4 為H；R5 為H；或R4 及R5 一起形成橋鍵，其為-CH2 CH2 -。 在一些實施例中，R4 為H；R5 為H。 在一些實施例中，R4 及R5 一起形成橋鍵，其為-CH2 CH2 -。 在一些實施例中，化合物具有式(IV)結構，或其醫藥學上可接受之鹽或溶劑合物：
Figure 02_image013
式(IV) 在一些實施例中，化合物具有式(V)結構，或其醫藥學上可接受之鹽或溶劑合物：
Figure 02_image015
式(V) 在一些實施例中，化合物具有式(VI)結構，或其醫藥學上可接受之鹽或溶劑合物：
Figure 02_image017
式(VI) 在一些實施例中，R4 為H；R5 為H；或R4 及R5 一起形成橋鍵，其為-CH2 CH2 -。 在一些實施例中，化合物具有式(VII)結構，或其醫藥學上可接受之鹽或溶劑合物：
Figure 02_image019
式(VII) 在一些實施例中，化合物具有式(VIII)結構，或其醫藥學上可接受之鹽或溶劑合物：
Figure 02_image021
式(VIII)。 在一些實施例中，R10 為H、D、F、-CN、-OH、C1 -C6 烷基、C1 -C6 烷氧基、C1 -C6 氟烷基、或-N(R12 )2 。在一些實施例中，R10 為H、D、F、-OH、C1 -C6 烷基、C1 -C6 烷氧基、或-N(R12 )2 。在一些實施例中，R10 為H、D、F、-CN、-OH、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-NH2 、-NH(CH3 )或-N(CH3 )2 。在一些實施例中，R10 為H、-OH、-CH3 、-OCH3 、-NH2 、-NH(CH3 )或-N(CH3 )2 。在一些實施例中，R10 為H、-OH或-NH2 。 在一些實施例中，R10 為-OH。 在一些實施例中，不超過兩個X2 、X3 、X4 、X4 為N。 在一些實施例中，若兩個X4 均為N，則X2 為CR2 且X3 為CR3 ；或若一個X4 為N且另一個X4 為CH，則僅X2 及X3 中之一者為N。 在一些實施例中，含有X2 、X3 、X4 、X4 之6員環在環中具有不超過兩個N原子。 在一些實施例中，X2 為CR2 ；X3 為CR3 或N；各X4 為CH；或各X4 為N；或一個X4 為N且另一個X4 為CH。 在一些實施例中，X2 為CR2 ；X3 為CR3 ；各X4 為CH；或各X4 為N；或一個X4 為N且另一個X4 為CH。 在一些實施例中，X2 為CR2 ；X3 為CR3 ；各X4 為CH。 在一些實施例中，R1 為H、D、F、Cl、-CN、-OH、-SH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H、-CO2 CH3 、-NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-SCH3 、-SCH2 CH3 、-SCH(CH3 )2 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH、-CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 或-CH2 N(CH3 )2 ；R2 為H、D、F、Cl、-CN、-OH、-SH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H、-CO2 CH3 、-NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-SCH3 、-SCH2 CH3 、-SCH(CH3 )2 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH、-CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 或-CH2 N(CH3 )2 ；或R1 及R2 與插入原子一起形成經取代或未經取代之5員稠環或經取代或未經取代之6員稠環，在該環中具有0至3個N原子及0至2個O或S原子，該環為經取代或未經取代之二氫呋喃基、經取代或未經取代之二氫吡咯基、經取代或未經取代之間二氧雜環戊烯基、經取代或未經取代之呋喃基、經取代或未經取代之噻吩基、經取代或未經取代之吡咯基、經取代或未經取代之噁唑基、經取代或未經取代之噻唑基、經取代或未經取代之咪唑基、經取代或未經取代之吡唑基、經取代或未經取代之三唑基、經取代或未經取代之異噁唑基或經取代或未經取代之異噻唑基、經取代或未經取代之哌啶基、經取代或未經取代之哌嗪基、經取代或未經取代之吡啶基、經取代或未經取代之嘧啶基、經取代或未經取代之吡嗪基或經取代或未經取代之噠嗪基；R3 為H、D、F、Cl、-CN、-OH、-SH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H、-CO2 CH3 、-NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-SCH3 、-SCH2 CH3 、-SCH(CH3 )2 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH、-CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 或-CH2 N(CH3 )2 。 在一些實施例中，R1 為H、D、F、Cl、-CN、-OH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H、-CO2 CH3 、-NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH、-CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 或-CH2 N(CH3 )2 ；R2 為H、D、F、Cl、-CN、-OH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H、-CO2 CH3 、-NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH、-CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 或-CH2 N(CH3 )2 ；或R1 及R2 與插入原子一起形成經取代或未經取代之5員稠環，在該環中具有0至3個N原子及0至2個O或S原子，該環為經取代或未經取代之二氫呋喃基、經取代或未經取代之間二氧雜環戊烯基、經取代或未經取代之呋喃基、經取代或未經取代之噻吩基、經取代或未經取代之吡咯基、經取代或未經取代之噁唑基、經取代或未經取代之噻唑基、經取代或未經取代之咪唑基、經取代或未經取代之吡唑基、經取代或未經取代之三唑基、經取代或未經取代之異噁唑基或經取代或未經取代之異噻唑基；R3 為H、D、F、Cl、-CN、-OH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H、-CO2 CH3 、-NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH、-CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 或-CH2 N(CH3 )2 。 在一些實施例中，R1 為H、D、F、Cl、-CN、-OH、-SH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-SCH3 、-SCH2 CH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 或-OCH2 CF3 ；R2 為H、D、F、Cl、-CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-SCH3 、-SCH2 CH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-OCH2 F、-OCHF2 、-OCF3 或-OCH2 CF3 ；R3 為H、D、F、Cl、-CH3 、-OCH3 、-SCH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 或-OCF3 。 在一些實施例中，R1 為H、D、F、Cl、-CN、-OH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 或-OCH2 CF3 ；R2 為H、D、F、Cl、-CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-OCH2 F、-OCHF2 、-OCF3 或-OCH2 CF3 ；R3 為H、D、F、Cl、-CH3 、-OCH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 或-OCF3 。 在一些實施例中，R1 為-OH、-SH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-CH3 、-OCH3 、-SCH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-OCH2 F、-OCHF2 、-OCF3 或-OCH2 CF3 ；R2 為H、D、F、Cl、-CH3 、-CD3 、-CH2 F、-CHF2 或-CF3 ；R3 為H。 在一些實施例中，R1 為-OH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-CH3 、-OCH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-OCH2 F、-OCHF2 、-OCF3 或-OCH2 CF3 ；R2 為H、D、F、Cl、-CH3 、-CD3 、-CH2 F、-CHF2 或-CF3 ；R3 為H。 在一些實施例中，R1 為H、D、F、Cl、-CN、-OH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-CH3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 或-OCF3 ；R2 為H、D、F、Cl、-CN、-OH、-CH3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 或-OCF3 。 在一些實施例中，R1 為-OH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-OCH3 、-OCD3 、-OCH2 F、-OCHF2 或-OCF3 ；R2 為F、Cl、-CN、-OH、-CH3 、-OCH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 或-OCF3 。在一些實施例中，R1 為-OH或-OCH3 ；R2 為H、D、F、Cl、-CH3 或-CF3 。 在一些實施例中，
Figure 02_image023
為
Figure 02_image025
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
或
Figure 02_image035
。在一些實施例中，
Figure 02_image037
為
Figure 02_image039
、
Figure 02_image041
或
Figure 02_image043
。 在一些實施例中，
Figure 02_image045
為
Figure 02_image047
。 在一些實施例中，
Figure 02_image049
為
Figure 02_image051
或
Figure 02_image053
。 在一些實施例中，
Figure 02_image055
為
Figure 02_image057
。 在一些實施例中，
Figure 02_image059
為
Figure 02_image061
。 在一些實施例中，
Figure 02_image063
為
Figure 02_image065
、
Figure 02_image067
或
Figure 02_image069
。 在一些實施例中，X2 為N；X3 為N；各X4 為CH。 在一些實施例中，
Figure 02_image071
為
Figure 02_image073
。 在一些實施例中，化合物具有式(IX)結構，或其醫藥學上可接受之鹽或溶劑合物：
Figure 02_image075
式(IX)。 在一些實施例中，R1 為H、D、F、Cl、-CN、-OH、-SH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H、-CO2 CH3 、-NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-SCH3 、-SCH2 CH3 、-SCH(CH3 )2 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH、-CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 或-CH2 N(CH3 )2 。 在一些實施例中，R1 為H、D、F、Cl、-CN、-OH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H、-CO2 CH3 、-NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH、-CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 或-CH2 N(CH3 )2 。 在一些實施例中，R1 為H、D、F、Cl、-CN、-OH、-SH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-SCH3 、-SCH2 CH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 或-OCH2 CF3 。 在一些實施例中，R1 為H、D、F、Cl、-CN、-OH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 或-OCH2 CF3 。 在一些實施例中，R1 為-OH、-SH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-CH3 、-OCH3 、-SCH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-OCH2 F、-OCHF2 、-OCF3 或-OCH2 CF3 。 在一些實施例中，R1 為-OH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-CH3 、-OCH3 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-OCH2 F、-OCHF2 、-OCF3 或-OCH2 CF3 。 在一些實施例中，R8 為H、D、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH(CH3 )CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-CD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-CHFCH3 、-CH2 CH2 F、-CH2 CH2 OH、-CH2 CH2 OCH3 、-CH2 CH2 NH2 、-CH2 CH2 NHCH3 、-CH2 CH2 N(CH3 )2 、-C(=O)CH3 、-C(=O)CH2 CH3 、-C(=O)CH(CH3 )2 、-CO2 CH3 、-CO2 CH2 CH3 、-CO2 CH(CH3 )2 、-C(=O)NHCH3 、-S(=O)2 CH3 、-S(=O)2 NHCH3 、經取代或未經取代之環丙基、經取代或未經取代之環丁基、經取代或未經取代之環戊基、經取代或未經取代之環己基、經取代或未經取代之氧雜環丁烷基、經取代或未經取代之四氫呋喃基、經取代或未經取代之四氫哌喃基或經取代或未經取代之四氫硫代哌喃基。 在一些實施例中，R8 為-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH(CH3 )CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-CD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-CHFCH3 、-CH2 CH2 F、-CH2 CH2 OH、-CH2 CH2 OCH3 、-CH2 CH2 NH2 、-CH2 CH2 NHCH3 、-CH2 CH2 N(CH3 )2 、經取代或未經取代之環丙基、經取代或未經取代之環丁基、經取代或未經取代之環戊基、經取代或未經取代之環己基、經取代或未經取代之氧雜環丁烷基、經取代或未經取代之四氫呋喃基或經取代或未經取代之四氫哌喃基。 在一些實施例中，R8 為H、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH(CH3 )CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-CD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-CHFCH3 、-CH2 CH2 F、-CH2 CH2 OH、-CH2 CH2 OCH3 、-CH2 CH2 NH2 、-CH2 CH2 NHCH3 、-CH2 CH2 N(CH3 )2 、環丙基、環丁基、環戊基、環己基、氧雜環丁烷基、四氫呋喃基或四氫哌喃基。在一些實施例中，R8 為H、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-CD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、環丙基、環丁基、環戊基、環己基、氧雜環丁烷基、四氫呋喃基或四氫哌喃基。在一些實施例中，R8 為-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 或環丙基。在一些實施例中，R8 為-CH(CH3 )2 或環丙基。 在一些實施例中，各R12 獨立地為H、C1 -C4 烷基、C1 -C4 氘代烷基、C1 -C4 氟烷基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之C2 -C6 雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基或經取代或未經取代之單環雜芳基。在一些實施例中，各R12 獨立地為H、C1 -C4 烷基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之C2 -C6 雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基、經取代或未經取代之單環雜芳基。在一些實施例中，各R12 獨立地為H、C1 -C4 烷基、C1 -C4 雜烷基、經取代或未經取代之C2 -C6 雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基或經取代或未經取代之單環雜芳基。在一些實施例中，各R12 獨立地為H、C1 -C4 烷基、或經取代或未經取代之C2 -C6 雜環烷基。在一些實施例中，各R12 獨立地為H或C1 -C4 烷基。 在一些實施例中，當兩個R12 附接於N原子時，則一個R12 為H或C1 -C4 烷基。在一些實施例中，當兩個R12 附接於N原子時，則一個R12 為H或C1 -C4 烷基，且另一個R12 為H、C1 -C4 烷基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之C2 -C6 雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基、經取代或未經取代之單環雜芳基。 在一些實施例中，當兩個R12 附接於N原子時，則一個R12 為H或C1 -C4 烷基，且另一個R12 為H、C1 -C4 烷基、C1 -C4 雜烷基、經取代或未經取代之C2 -C6 雜環烷基或經取代或未經取代之單環雜芳基。 在一些實施例中，當兩個R12 附接於N原子時，則一個R12 為H或C1 -C4 烷基，且另一個R12 為H、C1 -C4 烷基、C1 -C4 氘代烷基、C1 -C4 氟烷基、C1 -C4 雜烷基、經取代或未經取代之C3 -C6 環烷基、經取代或未經取代之C2 -C6 雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基、經取代或未經取代之單環雜芳基。 在一些實施例中，各R16 獨立地為H、D、F、Cl、-CN、-OH、-NH2 、-NH(CH3 )、-N(CH3 )2 、-NHS(=O)2 CH3 、-S(=O)2 CH3 、-C(=O)CH3 、-OC(=O)CH3 、-CO2 H、-CO2 CH3 、-NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-CH=CH2 、-CH=CHCH3 、-C≡CH、-C≡CCH3 、-C≡CCH2 CH3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 、-OCD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、-OCH2 F、-OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH、-CH2 CH2 OH、-CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 或-CH2 N(CH3 )2 、經取代或未經取代之環丙基、經取代或未經取代之環丁基、經取代或未經取代之環戊基、經取代或未經取代之環己基、經取代或未經取代之氮丙啶基、經取代或未經取代之氮雜環丁烷基、經取代或未經取代之吡咯啶基、經取代或未經取代之哌啶基、經取代或未經取代之四氫呋喃基、經取代或未經取代之四氫哌喃基、經取代或未經取代之四氫硫代哌喃基、經取代或未經取代之嗎啉基、經取代或未經取代之硫代嗎啉基或經取代或未經取代之哌嗪基。 在一些實施例中，各R16 獨立地為H、D、F、Cl、-CH3 、-CH2 CH3 、-CH(CH3 )2 、-C(CH3 )3 、-CD3 、-CH2 F、-CHF2 、-CF3 、-CH2 CF3 、經取代或未經取代之環丙基或經取代或未經取代之環丁基。 在一些實施例中，各R16 獨立地為H、D、F、Cl、-CH3 、-CH2 CH3 、-CD3 、-CH2 F、-CHF2 、-CF3 或-CH2 CF3 。 在一些實施例中，化合物具有式(X)結構，或其醫藥學上可接受之鹽或溶劑合物：
Figure 02_image077
式(X)。 在一些實施例中，化合物具有式(XI)結構，或其醫藥學上可接受之鹽或溶劑合物：
Figure 02_image079
式(XI)。 上文針對各種變數所述之基團的任何組合涵蓋於本文中。在整個說明書中，熟習此領域者會選擇基團及其取代基以得到穩定部分及化合物。 在一些實施例中，本文所述之化合物包括(但不限於)表1中所述之化合物。 表1.
Figure AA1
Figure AA2
Figure AA3
Figure AA4
Figure AA5
Figure AA7
Figure AA8
Figure AA9
 在一些實施例中，本文提供一種表1中所述之化合物的醫藥學上可接受之鹽或溶劑合物。 在一個態樣中，本文所述之化合物呈醫藥學上可接受之鹽形式。具有相同類型之活性的此等化合物之活性代謝物亦包括在本發明之範疇內。此外，本文所述之化合物可以非溶劑化以及在諸如水、乙醇及其類似者之醫藥學上可接受之溶劑下的溶劑化之形式存在。亦認為本文所呈現之化合物之溶劑化形式為本文所揭示。如本文所用，「醫藥學上可接受」係指不會消除化合物之生物活性或特性且相對無毒之物質，諸如載劑或稀釋劑，亦即將該物質投與個體而不會導致不合需要之生物效應或不會以有害方式與包含其之組合物之任一組分相互作用。 術語「醫藥學上可接受之鹽」係指由治療活性劑之陽離子形式以及適合陰離子組成的治療活性劑之形式，或在替代性實施例中，由治療活性劑之陰離子形式以及適合陽離子組成的治療活性劑之形式。Handbook of Pharmaceutical Salts: Properties, Selection and Use。International Union of Pure and Applied Chemistry, Wiley-VCH 2002。S.M. Berge、L.D. Bighley、D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19。P. H. Stahl及C. G. Wermuth編,Handbook of Pharmaceutical Salts: Properties, Selection and Use , Weinheim/Zürich: Wiley-VCH/VHCA, 2002。相較於非離子型物種，醫藥鹽通常較具可溶性且可較快速溶於胃及腸道汁液中且因此適用於固體劑型。此外，由於其可溶性通常為pH之功能，因此選擇性溶解於消化道之一部分或另一部分係可能的，且此能力可伴隨延遲及持續釋放特性之一個態樣而操控。此外，由於成鹽分子可以中性形式平衡，因此通過生物膜之傳遞可加以調整。 在一些實施例中，藉由使本文所述之化合物與酸反應獲得醫藥學上可接受之鹽以提供「醫藥學上可接受之酸加成鹽」。在一些實施例中，本文所述之化合物(亦即游離鹼形式)為鹼性的且與有機酸或無機酸反應。無機酸包括(但不限於)鹽酸、氫溴酸、硫酸、磷酸、硝酸及偏磷酸。有機酸包括(但不限於)1-羥基-2-萘甲酸；2,2-二氯乙酸；2-羥基乙磺酸；2-氧代戊二酸；4-乙醯胺基苯甲酸；4-胺基柳酸；乙酸；己二酸；抗壞血酸(L)；天冬胺酸(L)；苯磺酸；苯甲酸；樟腦酸(+)；樟腦-10-磺酸(+)；癸酸(羊蠟酸)；己酸(羊油酸)；辛酸(羊脂酸)；碳酸；肉桂酸；檸檬酸；環己胺磺酸；十二烷基硫酸；乙烷-1,2-二磺酸；乙磺酸；甲酸；反丁烯二酸；半乳糖二酸；龍膽酸；葡糖庚酸(D)；葡萄糖酸(D)；葡糖醛酸(D)；麩胺酸；戊二酸；甘油磷酸；乙醇酸；馬尿酸；異丁酸；乳酸(DL)；乳糖酸；月桂酸；順丁烯二酸；蘋果酸(- L)；丙二酸；杏仁酸(DL)；甲磺酸；反丁烯二酸單甲酯、萘-1,5-二磺酸；萘-2-磺酸；菸鹼酸；油酸；草酸；棕櫚酸；雙羥萘酸；磷酸；丙酸；焦麩胺酸(- L)；水楊酸；癸二酸；硬脂酸；丁二酸；硫酸；酒石酸(+ L)；硫氰酸；甲苯磺酸(p )；及十一碳烯酸。 在一些實施例中，本文所述之化合物經製備成氯鹽、硫酸鹽、溴鹽、甲磺酸鹽、順丁烯二酸鹽、檸檬酸鹽或磷酸鹽。 在一些實施例中，藉由使本文所述之化合物與鹼反應獲得醫藥學上可接受之鹽以提供「醫藥學上可接受之鹼加成鹽」。 在一些實施例中，本文所述之化合物為酸性的且與鹼反應。在此等情形下，本文所述之化合物之酸性質子係由金屬離子，例如鋰、鈉、鉀、鎂、鈣或鋁離子置換。在一些情況下，本文所述之化合物與有機鹼，諸如(但不限於)乙醇胺、二乙醇胺、三乙醇胺、緩血酸胺、葡甲胺、N-甲基葡糖胺、二環己胺、參(羥基甲基)甲胺配位。在其他情況下，本文所述之化合物與諸如(但不限於)精胺酸、離胺酸及其類似者之胺基酸形成鹽。用於與化合物形成鹽的可接受之無機鹼包括酸性質子，其包括(但不限於)氫氧化鋁、氫氧化鈣、氫氧化鉀、碳酸鈉、碳酸鉀、氫氧化鈉、氫氧化鋰及其類似者。在一些實施例中，本文所提供之化合物經製備成鈉鹽、鈣鹽、鉀鹽、鎂鹽、葡甲胺鹽、N-甲基葡糖胺鹽或銨鹽。 應瞭解，提及醫藥學上可接受之鹽包括溶劑加成形式。在一些實施例中，溶劑合物含有化學計量或非化學計量之溶劑，且在用諸如水、乙醇及其類似者之醫藥學上可接受之溶劑分離或純化化合物的過程中形成。當溶劑為水時形成水合物，或當溶劑為醇時形成醇化物。本文所述之化合物之溶劑合物宜在本文所述之過程中製備或形成。此外，本文所提供之化合物視情況以非溶劑化以及溶劑化形式存在。本文所述之方法及調配物包括使用本文所述之化合物的N -氧化物(適當時)、結晶型(亦稱為多晶型物)或醫藥學上可接受之鹽，以及具有相同類型之活性的此等化合物之活性代謝物。在一些實施例中，本文所述之化合物的有機自由基(例如烷基、芳環)上之位點易受不同代謝反應影響。將合適取代基併入有機自由基上將減少、最小化或消除此代謝路徑。在特定實施例中，降低或消除芳環對代謝反應之易感性的合適取代基僅舉例而言為鹵素、氘、烷基、鹵烷基或氘代烷基。 在另一實施例中，本文所述化合物以同位素標記(例如用放射性同位素)或藉由其他手段標記，包括(但不限於)使用發色團或螢光部分、生物發光標記或化學發光標記。 本文所述之化合物包括經同位素標記之化合物，其與本文所呈現之多個式及結構中所述之彼等化合物相同，但實際上一或多個原子經原子質量或質量數不同於自然界中常見之原子質量或質量數之原子置換。可併入本發明化合物中之同位素之實例包括氫、碳、氮、氧、氟及氯之同位素，諸如2 H、3 H、13 C、14 C、15 N、18 O、17 O、35 S、18 F、36 Cl。在一個態樣中，經同位素標記之本文所述化合物(例如其中併有諸如3 H及14 C之放射性同位素之化合物)適用於藥物及/或底物組織分佈分析。在一個態樣中，用諸如氘之同位素取代得到由較高代謝穩定性產生之某些治療優點，諸如增加之活體內半衰期或降低之劑量需求。在一些實施例中，本文所述之化合物之一或多個氫原子經氘置換。在一些實施例中，本文所述之化合物具有一或多個立體中心，且各立體中心以R或S組態任一者獨立存在。本文所呈現之化合物包括所有非對映異構體、對映異構體、滯轉異構體及差向異構體以及其合適混合物。本文所提供之化合物及方法包括所有順式、反式、同側、對側、E型(entgegen，E)及Z型(zusammen，Z)異構體以及其合適混合物。 必要時藉由諸如立體選擇性合成及/或藉由對掌性層析管柱分離立體異構體之方法獲得獨立立體異構體。在某些實施例中，如下將本文所述之化合物製備為其獨立立體異構體：使化合物之外消旋混合物與光學活性解析劑反應以形成非對映異構化合物/鹽對、分離非對映異構體且回收光學純對映異構體。在一些實施例中，使用本文所述之化合物之共價非對映異構衍生物解析對映異構體。在另一實施例中，根據可溶性差異藉由分離/解析技術分離非對映異構體。在其他實施例中，藉由層析或藉由形成非對映異構鹽及藉由再結晶或層析分離或其任何組合來分離立體異構體。Jean Jacques、Andre Collet、Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons公司, 1981。在一些實施例中，立體異構體係藉由立體選擇性合成獲得。 在一些實施例中，本文所述之化合物以前藥形式製備。「前藥」係指活體內轉化成母體藥物之藥劑。前藥通常適用，因為在一些情況下其比母體藥物更容易投與。其例如藉由口服而為生物可用的，而母體藥物則不然。前藥可為轉運體之底物。進一步地或替代地，相比於母體藥物，前藥亦具有在醫藥組合物中之經改良之可溶性。在一些實施例中，前藥之設計會增加有效水溶性。前藥之實例為(但不限於)本文所述之化合物，其以酯(「前藥」)形式投與，但隨後發生代謝水解得到活性實體。前藥之另一實例為鍵結至酸基之短肽(聚胺基酸)，其中肽會發生代謝展示活性部分。在某些實施例中，在活體內投與後，前藥化學轉化成化合物之生物學、醫藥學或治療學活性之形式。在某些實施例中，前藥由一或多個步驟或製程酶促代謝為化合物之生物學、醫藥學或治療學活性之形式。本文所述之化合物之前藥包括(但不限於)酯、醚、碳酸酯、硫碳酸酯、N-醯基衍生物、N-醯氧基烷基衍生物、三級胺之四級衍生物、N-曼尼希鹼(N-Mannich base)、希夫鹼(Schiff base)、胺基酸共軛物、磷酸酯及磺酸酯。參見例如 Design of Prodrugs, Bundgaard, A.編, Elseview, 1985及Method in Enzymology, Widder, K.等人編; Academic, 1985, 第42卷, 第309-396頁；Bundgaard, H. 「Design and Application of Prodrugs」於A Textbook of Drug Design and Development, Krosgaard-Larsen及H. Bundgaard編, 1991, 第 5章, 第113-191頁；及Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38各文獻以引用之方式併入本文中。在一些實施例中，使用本文所揭示之化合物中之羥基形成前藥，其中該羥基併入醯氧基烷基酯、烷氧基羰氧基烷基酯、烷基酯、芳基酯、磷酸酯、糖酯、醚及其類似者中。在一些實施例中，本文所揭示之化合物中之羥基為前藥，其中羥基隨後活體內代謝以得到羧酸基。在一些實施例中，使用羧基提供酯或醯胺(亦即前藥)，其隨後活體內代謝以得到羧酸基。在一些實施例中，本文所述之化合物製備為烷基酯前藥。 本文所述之化合物之前藥形式包括於申請專利範圍之範疇內，其中如本文所闡述，前藥活體內代謝以產生本文所述之化合物。在一些情況下，本文所述之化合物中之一些為另一衍生物或活性化合物之前藥。 本文所述之化合物之前藥形式包括於申請專利範圍之範疇內，其中如本文所闡述，前藥活體內代謝以產生本文所述之化合物。在一些情況下，本文所述之化合物中之一些為另一衍生物或活性化合物之前藥。在一些實施例中，本文所揭示之化合物之前藥准許將化合物靶向遞送至胃腸道之特定區域。藉由藥物之結腸代謝形成藥理學活性代謝物為結腸特異性藥物遞送系統之常用「前藥」方法。 在一些實施例中，藉由以使得口服後，部分在胃及小腸中保持完好之方式在藥物與載劑之間形成共價鍵來形成前藥。此方法涉及形成前藥，其為母體藥物分子之藥理學非活性衍生物，需要在生物環境中自發性或酶促轉化以釋放活性藥物。相比於母體藥物分子，前藥之形成具有經改良之遞送特性。來自上胃腸道之有害環境的某些藥物之穩定性問題可藉由前藥形成而得到消除，其在達至結腸中後轉化成母體藥物分子。經由位點特異性前藥活化之位點特異性藥物遞送可藉由利用目標位點處之一些特定特性，諸如相對於前藥-藥物轉化之非靶組織，某些酶之經變化之pH或高活性來實現。 在一些實施例中，藥物與載劑之共價鍵形成共軛物。此類共軛物包括(但不限於)偶氮鍵共軛物、糖苷共軛物、葡萄糖苷酸共軛物、環糊精共軛物、葡聚糖共軛物或胺基酸共軛物。 在額外或其他實施例中，本文所述之化合物在投與有需要之生物體後發生代謝以產生代謝物，隨後代謝物用以產生所需作用，包括所需治療作用。 本文所揭示之化合物之「代謝物」為當化合物代謝時形成之化合物的衍生物。術語「活性代謝物」係指當化合物代謝時形成之化合物的生物活性衍生物。如本文所用，術語「代謝」係指過程(包括(但不限於)水解反應及酶催化之反應)之總和，藉由該過程之總和特定物質經有機體改變。因此，酶可使化合物產生特定結構變化。舉例而言，細胞色素P450催化多種氧化及還原反應，而二磷酸尿苷葡糖醛酸轉移酶催化活化葡糖醛酸分子向芳族醇、脂族醇、羧酸、胺及游離硫氫基轉移。本文所揭示之化合物之代謝物視情況藉由以下來鑑別：向主體投與化合物且分析主體之組織樣本，或將化合物與肝細胞一起活體外培育且分析所得化合物。 在一些實施例中，本文所述之化合物在自胃腸道吸收之後快速代謝為顯著降低FXR促效劑活性之代謝物。 在額外或其他實施例中，化合物在血漿中快速代謝。 在額外或其他實施例中，化合物藉由腸快速代謝。 在額外或其他實施例中，化合物藉由肝臟快速代謝。化合物之合成 本文所述之化合物使用標準合成技術或使用此項技術中已知之方法以及本文所述之方法來合成。 除非另外指示，否則採用習知之質譜、NMR、HPLC、蛋白質化學、生物化學、重組DNA技術及藥理學方法。 使用標準有機化學技術，諸如例如March's Advanced Organic Chemistry, 第6版, John Wiley and Sons公司中所述之技術來製備化合物。可採用用於本文所述之合成性轉化的替代反應條件，諸如溶劑變體、反應溫度、反應時間以及不同化學試劑及其他反應條件。起始物質購自商業來源或容易製備。 詳述適用於製備本文所述之化合物的反應物之合成或提及描述該製備之文章的適合參考書及論文包括例如「Synthetic Organic Chemistry」, John Wiley & Sons公司, New York；S. R. Sandler等人, 「Organic Functional Group Preparations」, 第2版, Academic Press, New York, 1983；H. O. House, 「Modern Synthetic Reactions」, 第2版, W. A. Benjamin公司. Menlo Park, Calif. 1972；T. L. Gilchrist, 「Heterocyclic Chemistry」, 第2版, John Wiley & Sons, New York, 1992；J. March, 「Advanced Organic Chemistry: Reactions, Mechanisms and Structure」, 第4版, Wiley-Interscience, New York, 1992。詳述適用於製備本文所述之化合物的反應物之合成或提及描述該製備之文章的其他適合參考書及論文包括例如Fuhrhop, J.及Penzlin G. 「Organic Synthesis: Concepts, Methods, Starting Materials」, 第二版、修訂版及增補版(1994) John Wiley & Sons ISBN: 3-527-29074-5；Hoffman, R.V. 「Organic Chemistry, An Intermediate Text」 (1996) Oxford University Press, ISBN 0-19-509618-5；Larock, R. C. 「Comprehensive Organic Transformations: A Guide to Functional Group Preparations」 第2版(1999) Wiley-VCH, ISBN: 0-471-19031-4；March, J. 「Advanced Organic Chemistry: Reactions, Mechanisms, and Structure」 第4版(1992) John Wiley & Sons, ISBN: 0-471-60180-2；Otera, J. (編) 「Modern Carbonyl Chemistry」 (2000) Wiley-VCH, ISBN: 3-527-29871-1；Patai, S. 「Patai's 1992 Guide to the Chemistry of Functional Groups」 (1992) Interscience ISBN: 0-471-93022-9；Solomons, T. W. G. 「Organic Chemistry」 第7版(2000) John Wiley & Sons, ISBN: 0-471-19095-0；Stowell, J.C., 「Intermediate Organic Chemistry」第2版(1993) Wiley-Interscience, ISBN: 0-471-57456-2；「Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia」 (1999) John Wiley & Sons, ISBN: 3-527-29645-X, 8卷；「Organic Reactions」 (1942-2000) John Wiley & Sons, 超過55卷；及「Chemistry of Functional Groups」 John Wiley & Sons, 73卷。 藉由下文流程1至流程11中所述之通用合成途徑製備本文所述之化合物。 在一些實施例中，如流程1中所概述製備用於製備本文所述之化合物的中間物。流程 1
Figure 02_image213
在流程1中，取代基X2 、X3 、X4 、R1 及R2 係如本文所述。在一些實施例中，X2 為C-R2 ，X3 為C-H且各X4 為C-H。在一些實施例中，X為鹵化物。在一些實施例中，X為氯、溴或碘。 在一些實施例中，
Figure 107108918-A0304-12-0030-1
酸酯I - 2 與鹵化物I - 1 在適合的經金屬催化之交叉偶合反應條件下反應，得到I - 3 。在一些實施例中，適合的經金屬催化之交叉偶合條件包括使用鈀。在一些實施例中，適合的經鈀催化之交叉偶合反應條件包括Pd(dppf)Cl2 或Pd(PPh3 )4 及合適鹼及合適溶劑或溶劑混合物持續合適時間且處於合適溫度下。在一些實施例中，鹼為無機鹼。在一些實施例中，無機鹼為碳酸鹽鹼，諸如Na2 CO3 或Cs2 CO3 。在一些實施例中，合適溶劑或溶劑混合物為二噁烷、乙腈、DME/EtOH或乙醇。在一些實施例中，合適時間及合適溫度為約2小時至約18小時(隔夜)，在約50℃或約100℃下。 在一些實施例中，使I - 3 經歷適合氫化條件，之後在合適酸性條件下處理，得到環己酮I - 4 。在一些實施例中，適合氫化條件包括使用鈀。經鈀催化之氫化條件包括在合適溫度下在適合溶劑，諸如EtOAc、乙醇、甲醇或此等溶劑之組合中使用10% Pd/C及氫氣(1 atm)持續合適時間量。在一些實施例中，約室溫下之合適時間量為約4.5小時至約18小時(隔夜)。在一些實施例中，合適酸性條件包括在合適溫度下甲酸之水及甲苯溶液持續適合時間量。在一些實施例中，合適溫度下之適合時間量為在約120℃下約4小時。在一些實施例中，合適溫度下之適合時間量在回流下為約18小時(隔夜)。在一些實施例中，合適酸性條件包括在合適溫度下PPTS之丙酮及水溶液持續適合時間量。在一些實施例中，合適溫度下之適合時間量為在約60℃下約10小時。在一些實施例中，合適酸性條件包括在合適溫度下3 M HCl及THF持續適合時間量。在一些實施例中，合適溫度下之適合時間量為在約60℃下約3小時至約隔夜。 在一些實施例中，使I - 4 在適合之一碳同系化條件下反應，得到I - 5 。在一些實施例中，適合之一碳同系化條件包括使用鏻試劑。在一些實施例中，適合之一碳同系化條件包括在合適溫度下用合適鹼、用合適溶劑預處理(甲氧基甲基)三苯基鏻[Ph3 P+ CH2 OCH3 Cl- ]持續合適時間量，之後添加環己酮I - 4 。在一些實施例中，合適鹼為NaHMDS。在一些實施例中，合適鹼為KHMDS或LiHMDS。在一些實施例中，合適溶劑為THF。在一些實施例中，添加環己酮I - 4 之前，合適溫度下之合適時間量為在約0℃下約30分鐘至約2小時。在一些實施例中，添加I - 4 之後，使反應在約0℃下再繼續約30分鐘至約3小時。在一些實施例中，將反應升溫至約室溫隔夜。 在一些實施例中，隨後使I - 5 處於適合酸性條件下，得到順式醛及反式醛I - 6 。在一些實施例中，適合酸性條件包括在約120℃至約130℃下甲酸之水/甲苯溶液持續約2小時至約隔夜。在一些實施例中，適合酸性條件包括在約60℃下HCl之THF溶液持續約1小時或約6小時。在一些實施例中，進一步使醛I - 6 處於合適鹼性條件下，得到主要為反式之醛I - 6 。在一些實施例中，合適鹼性條件包括在合適溫度下NaOH於適合溶劑混合物，諸如H2 O、EtOH及PhMe中持續適合時間量。在一些實施例中，使用THF代替PhMe。在一些實施例中，合適溫度下之合適時間量為在約室溫下約5.5小時至約隔夜。在一些實施例中，合適鹼性條件包括在合適溫度下NaOMe於適合溶劑，諸如MeOH中持續適合時間量。在一些實施例中，合適溫度下之合適時間量為在約室溫下約4小時至約18小時。在一些實施例中，經由結晶或層析進一步純化，得到純反式醛I - 6 。 在一些實施例中，如流程2中所概述製備用於製備本文所述之化合物的中間物。流程 2
Figure 02_image215
在流程2中，取代基X2 、X3 、X4 、R1 、R2 及m係如本文所述。在一些實施例中，X2 為C-R2 ，X3 為C-H且各X4 為C-H。在一些實施例中，R6 為烷基。在一些實施例中，R6 為甲基。在一些實施例中，X為鹵素。在一些實施例中，X為氯、溴或碘。 在一些實施例中，將II - 1 冷卻至適合溫度，在適合金屬-鹵素交換條件下且在合適溫度下與合適溶劑反應持續合適時間，且隨後與合適酮II - 2 反應持續合適時間且在合適溫度下反應，得到II - 3 。在一些實施例中，適合金屬-鹵素交換條件包括有機金屬試劑。在一些實施例中，合適溶劑為THF。在一些實施例中，有機金屬試劑為烷基鋰。在一些實施例中，烷基鋰為正丁基鋰。在一些實施例中，將II - 1 冷卻至約-78℃，之後添加有機金屬試劑。在一些實施例中，在約-78℃下使II - 1 反應持續約兩小時，之後添加合適酮II - 2 。在一些實施例中，在添加酮II - 2 之後，使中間有機金屬試劑反應持續約3小時。在一些實施例中，在添加酮II - 2 之後，使中間有機金屬試劑在約-78℃下反應。 在一些實施例中，使醇II - 3 在合適還原條件下且在合適溫度下與合適溶劑反應持續合適時間，形成脫水產物與還原產物之混合物。在一些實施例中，條件包括使用三氟乙酸及氫化矽烷。在一些實施例中，氫化矽烷為三乙基矽烷。在一些實施例中，合適溶劑為二氯甲烷。在一些實施例中，溫度為約0℃至約室溫或為約0℃。在一些實施例中，合適時間為約隔夜或約1小時。在一些實施例中，使還原產物與脫水產物之混合物在合適條件下且在合適溫度下與合適溶劑反應持續合適時間以形成酮。在一些實施例中，合適溶劑為甲酸、甲苯及水混合物。在一些實施例中，合適溫度為約130℃。在一些實施例中，合適時間為約隔夜。在一些實施例中，合適溶劑為甲酸、THF及水混合物。在一些實施例中，合適溫度為約80℃。在一些實施例中，合適時間為約18小時。在一些實施例中，用合適溶劑使含有脫水副產物之此酮在適合還原條件下且在合適溫度下完全還原持續合適時間以形成II - 4 。在一些實施例中，合適還原條件包括使用氫氣作為還原劑。在一些實施例中，氫氣處於約15 psi或約30 psi之壓力下。在一些實施例中，烯烴還原包括使用鈀催化劑。在一些實施例中，鈀催化劑為10%鈀/碳。在一些實施例中，溶劑為乙酸乙酯及濃HCl。在一些實施例中，溶劑為乙酸乙酯。在一些實施例中，溫度為約室溫。在一些實施例中，合適時間為約30分鐘至約18小時。 在一些實施例中，在合適溶劑中且在合適溫度下用親電子劑R6 X預處理II - 4 。在一些實施例中，親電子劑為烷基鹵化物。在一些實施例中，X為氯、溴或碘。在一些實施例中，親電子劑為甲基碘化物。在一些實施例中，溫度為約-78℃。在一些實施例中，混合物進一步與鹼反應持續合適時間且在合適溫度下反應以形成烷基化產物。在一些實施例中，鹼為二異丙基胺化鋰。在一些實施例中，合適時間為約2小時。在一些實施例中，溫度為約-78℃。在一些實施例中，歷經適合時間量進一步使混合物升溫至約室溫。在一些實施例中，適合時間量為約隔夜。 在一些實施例中，如流程1中所述，將酮II - 4 轉化成醛II - 7 。 或者在一些實施例中，使II - 4 在適合之一碳同系化條件下反應，得到II - 5 。在一些實施例中，適合之一碳同系化條件包括使用鏻試劑。在一些實施例中，適合之一碳同系化條件包括在合適溫度下用合適鹼在合適溶劑中預處理甲基三苯基溴化鏻[Ph3 P+ CH3 Br- ]持續合適時間量，之後添加環己酮II - 4 。在一些實施例中，合適鹼為有機鹼。在一些實施例中，合適鹼為醇鹽鹼。在一些實施例中，合適鹼為第三丁醇鉀。在一些實施例中，合適溶劑為甲苯。在一些實施例中，添加酮之前的合適時間為約30分鐘。在一些實施例中，添加酮之前的反應溫度為約100℃。在一些實施例中，在合適溫度下將酮II - 4 添加於合適溶劑中且持續合適時間量。在一些實施例中，添加酮之後，反應溫度為約50℃。在一些實施例中，將酮添加於甲苯中。在一些實施例中，使酮在適合溫度下進一步反應持續適合時間量。在一些實施例中，使酮在約100℃下進一步反應。在一些實施例中，使酮進一步反應持續約2小時。 在一些實施例中，使烯烴II - 5 經歷水合條件以形成II - 6 。在一些實施例中，水合條件包括用還原劑之後用氧化劑加以處理。在一些實施例中，在合適溫度下使還原劑與II - 5 在合適溶劑中反應且持續合適時間量。在一些實施例中，還原劑為硼烷。在一些實施例中，還原劑為BH3 -SMe2 。在一些實施例中，使還原劑與II - 5 在THF中反應。在一些實施例中，反應溫度為約0℃。在一些實施例中，添加還原劑之前使反應進行持續約一小時。在一些實施例中，反應在約室溫下進一步持續進行。在一些實施例中，反應進一步持續約3小時。在一些實施例中，在合適溫度下在合適溶劑中用氧化劑進一步氧化中間硼烷產物以形成醇II - 6 且持續合適時間量。在一些實施例中，氧化劑為30% H2 O2 。在一些實施例中，氧化反應在鹼存在下進行。在一些實施例中，鹼為NaOH。在一些實施例中，溶劑為H2 O。在一些實施例中，合適時間量為約隔夜。在一些實施例中，合適溫度為約室溫。 在一些實施例中，使醇II - 6 經歷氧化劑以形成醛II - 7 。在一些實施例中，氧化劑為斯文氧化劑(Swern oxidant)，其在合適溫度下處於合適溶劑中且持續合適時間量。在一些實施例中，斯文氧化劑用DMSO及乙二醯氯形成。在一些實施例中，合適溶劑為二氯甲烷。在一些實施例中，針對斯文氧化劑形成之合適溫度為約-78℃。在一些實施例中，針對斯文氧化劑形成之合適時間為30分鐘。在一些實施例中，使II - 6 與斯文氧化劑在約 -78℃下反應。在一些實施例中，使II - 6 與斯文氧化劑反應持續約一小時。在一些實施例中，隨後在合適溫度下添加鹼持續合適時間量。在一些實施例中，鹼為胺鹼。在一些實施例中，胺鹼為三乙胺。在一些實施例中，合適溫度為約-78℃。在一些實施例中，添加鹼之後的合適反應時間為約一小時。在一些實施例中，氧化反應產生呈順式及反式異構體之混合物形式的II - 7 。 在一些實施例中，在合適溫度下在合適溶劑中且持續合適時間用合適試劑將II - 7 之順式/反式混合物平衡為主要為反式之II - 7 。在一些實施例中，合適試劑為鹼。在一些實施例中，鹼為無機鹼。在一些實施例中，鹼為氫氧化鈉。在一些實施例中，合適溶劑為混合物，諸如H2 O、EtOH及PhMe。在一些實施例中，合適時間為約3小時。在一些實施例中，合適溫度為約室溫。在一些實施例中，經由結晶或層析進一步純化，得到純反式醛II - 7 。 在一些實施例中，如流程3中所概述製備用於製備本文所述之化合物的中間物。流程 3
Figure 02_image217
在流程3中，取代基X2 、X3 、X4 、R1 、R2 及m係如本文所述。在一些實施例中，X2 為C-R2 ，X3 為C-H且各X4 為C-H。在一些實施例中，R6 為烷基。在一些實施例中，R6 為甲基。 在一些實施例中，在合適溫度下在合適溶劑中用鹼處理酮III - 1 持續合適時間量，以用合適鹼形成烯醇化物。在一些實施例中，鹼為有機鹼。在一些實施例中，有機鹼為LiHMDS。在一些實施例中，烯醇化物形成在約-78℃下進行。在一些實施例中，合適溶劑為THF。在一些實施例中，合適時間為約一小時。在一些實施例中，在合適溫度下在合適溶劑中使酮III - 1 之烯醇化物與適合親電子劑反應持續合適時間量，形成烯醇醚III - 2 。在一些實施例中，親電子劑形成硫酸酯。在一些實施例中，親電子劑為PhNTf2 。在一些實施例中，合適溫度為約-78℃且合適時間為約2小時。在一些實施例中，歷經適合時段使反應進一步升溫至適合溫度。在一些實施例中，適合溫度為約室溫持續約隔夜。 在一些實施例中，使
Figure 107108918-A0304-12-0030-1
酸III - 3 與烯醇三氟甲磺酸酯III - 2 在適合的經金屬催化之交叉偶合反應條件下反應，得到III - 4 。在一些實施例中，適合的經金屬催化之交叉偶合條件包括鈀。在一些實施例中，適合的經鈀催化之交叉偶合反應條件包括Pd(dppf)Cl2 及合適鹼及合適溶劑持續合適時間且處於合適溫度下。在一些實施例中，鹼為無機鹼。在一些實施例中，無機鹼為碳酸鹽鹼，諸如Na2 CO3 。在一些實施例中，合適溶劑為二噁烷/水混合物。在一些實施例中，合適時間及合適溫度為約6小時，在約30℃下。 在一些實施例中，使III - 4 處於適合烯烴還原條件下，之後在合適酸性條件下加以處理，得到環己酮III - 5 。在一些實施例中，適合還原條件包括經鈀催化之氫化條件。在一些實施例中，經鈀催化之氫化條件包括在合適溫度下在適合溶劑，諸如EtOAc中使用10% Pd/C及氫氣(1 atm)持續合適時間量。在一些實施例中，約室溫下之合適時間量為約隔夜。在一些實施例中，合適酸性條件包括在合適溫度下使用甲酸之水及甲苯溶液持續適合時間量。在一些實施例中，合適溫度下之適合時間量為在約120℃下約隔夜。 在一些實施例中，如流程1及流程2中所示，酮III - 5 分別轉化為醛I - 6 或醛II - 7 。 在一些實施例中，如流程4中所概述製備本文所述之化合物。流程 4
Figure 02_image219
在流程4中，取代基Y、X1 、X2 、X3 、X4 、R1 、R2 及R8 係如本文所述。在一些實施例中，X2 為C-R2 ，X3 為C-H且各X4 為C-H。在一些實施例中，X為鹵化物。在一些實施例中，X為碘或溴。 在一些實施例中，使反式醛IV - 1 與合適苯胺IV - 2 在適合還原胺化條件下反應。在一些實施例中，適合還原胺化條件包括在合適溫度下在合適溶劑，諸如DCE或DCM中使用適合還原劑及乙酸持續適合時間量。在一些實施例中，使用NaBH(OAc)3 作為還原劑。在一些實施例中，合適溫度為約室溫。在一些實施例中，適合時間量為約一小時至約2.5小時。在一些實施例中，適合反應條件包括在合適溫度下乙酸於合適溶劑，諸如甲醇中持續適合時間量，之後添加還原劑。在一些實施例中，合適溫度及時間為約室溫持續約5分鐘至約4小時。在一些實施例中，反應隨後進一步經歷適合還原劑，諸如NaBH3 CN持續合適時間且在合適溫度下進行。在一些實施例中，約室溫下之合適時間量為約隔夜。 在一些實施例中，用醯氯醯化胺IV - 3 ，得到化合物IV - 4 。適合醯化條件包括(但不限於)在適合溶劑，諸如DCM或甲苯中且在適合溫度，諸如約室溫至約80℃下使用適合鹼，諸如TEA或吡啶持續合適時間量，諸如持續約1小時至約隔夜。在一些實施例中，使用吡啶作為鹼及溶劑兩者。其他適合條件包括添加DMAP。在一些實施例中，可使用硼-鹵素交換條件由IV - 4 製備
Figure 107108918-A0304-12-0030-1
酸酯IV - 5 。適合之硼-鹵素交換條件包括(但不限於)使用適合有機金屬試劑及適合硼試劑。在一些實施例中，適合有機金屬試劑包括鈀。在一些實施例中，適合硼試劑包括雙(頻哪醇根基)二硼。在一些實施例中，適合的經鈀催化之硼-鹵素交換條件包括Pd(dppf)Cl2 及合適鹼於合適溶劑中持續合適時間且處於合適溫度下。在一些實施例中，鹼為無機鹼。在一些實施例中，無機鹼為乙酸鹽鹼，諸如KOAc。在一些實施例中，合適溶劑為甲苯。在一些實施例中，合適時間及合適溫度為約4小時至約隔夜及約100℃至約115℃。在一些實施例中，使
Figure 107108918-A0304-12-0030-1
酸酯IV - 5 與雜芳基鹵化物在適合的經金屬催化之交叉偶合反應條件下反應，得到IV - 6 。在一些實施例中，雜芳基鹵化物為雜芳基溴化物。在一些實施例中，雜芳基鹵化物為吡唑基鹵化物。在一些實施例中，適合的經金屬催化之交叉偶合條件包括使用鈀。在一些實施例中，適合的經鈀催化之交叉偶合反應條件包括Pd(dppf)Cl2 或Pd(PPh3 )4 及合適鹼及合適溶劑持續合適時間且處於合適溫度下。在一些實施例中，鹼為無機鹼。在一些實施例中，無機鹼為碳酸鹽鹼，諸如K2 CO3 、Na2 CO3 或Cs2 CO3 。在一些實施例中，合適溶劑為二噁烷或DMF。在一些實施例中，水為共溶劑。在一些實施例中，合適時間及合適溫度為約10分鐘至約4小時，在約50℃至約80℃下。在一些實施例中，合適時間及合適溫度為約0.5小時至約6小時，在約80℃下。在一些實施例中，使芳基鹵化物IV - 4 與硼試劑在適合的經金屬催化之交叉偶合反應條件下反應，得到IV - 6 。在一些實施例中，硼試劑為雜芳基
Figure 107108918-A0304-12-0030-1
酸。在一些實施例中，硼試劑為雜芳基
Figure 107108918-A0304-12-0030-1
酸酯。在一些實施例中，硼試劑為雜芳基頻哪基
Figure 107108918-A0304-12-0030-1
酸酯。在一些實施例中，雜芳基硼試劑為吡唑基硼試劑。在一些實施例中，適合的經金屬催化之交叉偶合條件包括鈀。在一些實施例中，適合的經鈀催化之交叉偶合反應條件包括Pd(dppf)Cl2 或Pd(PPh3 )4 及合適鹼及合適溶劑持續合適時間且處於合適溫度下。在一些實施例中，鹼為無機鹼。在一些實施例中，無機鹼為碳酸鹽鹼，諸如Cs2 CO3 、Na2 CO3 或K2 CO3 。在一些實施例中，合適溶劑為二噁烷/水或DMF/水混合物。在一些實施例中，合適時間及合適溫度為約10分鐘至約2小時，在約50℃至約100℃下或在約80℃下。在一些實施例中，Y含有經保護之醇。在一些實施例中，Y受矽烷基醚保護。在一些實施例中，使用適合脫保護條件，包括合適溶劑、溫度及時間來移除保護基以產生游離醇，產生IV - 6 。在一些實施例中，適合之脫保護條件包括使用HCl水溶液。在一些實施例中，合適溶劑為水、THF、甲醇或各溶劑之組合。在一些實施例中，合適溫度下之合適時間為在約0℃至約室溫下約30分鐘至約1小時。 在一些實施例中，如流程5中所概述製備本文所述之化合物。流程 5
Figure 02_image221
在流程5中，取代基Y、X1 、X2 、X3 、X4 、R1 、R2 、R4 、R5 、R6 、R8 及m係如本文所述。在一些實施例中，X2 為C-R2 ，X3 為C-H且各X4 為C-H。在一些實施例中，X為鹵化物。在一些實施例中，X為碘或溴。在一些實施例中，R為烷基。在一些實施例中，R為氫。在一些實施例中，使硼試劑V - 1 與雜芳基鹵化物V - 2 在適合的經金屬催化之交叉偶合反應條件下反應，得到V - 3 。在一些實施例中，雜芳基鹵化物為雜芳基溴化物或雜芳基碘化物。在一些實施例中，雜芳基鹵化物為吡唑基鹵化物。在一些實施例中，適合的經金屬催化之交叉偶合條件包括鈀。在一些實施例中，適合的經鈀催化之交叉偶合反應條件包括Pd(dppf)Cl2 及合適鹼及合適溶劑持續合適時間且處於合適溫度下。在一些實施例中，鹼為無機鹼。在一些實施例中，無機鹼為碳酸鹽鹼，諸如K2 CO3 。在一些實施例中，合適溶劑為二噁烷/水混合物。在一些實施例中，合適時間及合適溫度為約4小時，在約80℃下。在一些實施例中，使芳基鹵化物V - 4 與硼試劑V - 5 在適合的經金屬催化之交叉偶合反應條件下反應，得到V - 3 。在一些實施例中，硼試劑為雜芳基
Figure 107108918-A0304-12-0030-1
酸。在一些實施例中，硼試劑為雜芳基
Figure 107108918-A0304-12-0030-1
酸酯。在一些實施例中，硼試劑為雜芳基頻哪基
Figure 107108918-A0304-12-0030-1
酸酯。在一些實施例中，雜芳基硼試劑為吡唑基硼試劑。在一些實施例中，適合的經金屬催化之交叉偶合條件包括鈀。在一些實施例中，適合的經鈀催化之交叉偶合反應條件包括Pd(dppf)Cl2 及合適鹼及合適溶劑持續合適時間且處於合適溫度下。在一些實施例中，鹼為無機鹼。在一些實施例中，無機鹼為碳酸鹽鹼，諸如K2 CO3 。在一些實施例中，合適溶劑為二噁烷/水混合物。在一些實施例中，合適時間及合適溫度為約20分鐘，在約90℃下。在一些實施例中，使醛與苯胺V - 3 在適合之還原胺化條件下反應以形成胺V - 9 。在一些實施例中，適合之還原胺化條件包括在合適溫度下在合適溶劑，諸如DCE或DCM中使用適合還原劑持續適合時間量。在一些實施例中，添加乙酸。在一些實施例中，使用NaBH(OAc)3 作為還原劑。在一些實施例中，合適溫度為約室溫。在一些實施例中，適合時間量為約一小時至約隔夜。在一些實施例中，適合反應條件包括在合適溫度下乙酸於合適溶劑，諸如甲醇中持續適合時間量，之後添加還原劑。在一些實施例中，合適溫度及時間為約室溫持續約5分鐘至約4小時。在一些實施例中，反應經歷適合還原劑，諸如NaBH3 CN持續合適時間且在合適溫度下進行。在一些實施例中，約室溫下之合適時間量為約隔夜。 在一些實施例中，用醯氯醯化苯胺V - 9 ，得到醯胺V - 10 。適合醯化條件包括(但不限於)在適合溶劑，諸如DCM、甲苯或吡啶中且在適合溫度，諸如約0℃至約50℃或約0℃至約80℃下使用適合鹼，諸如TEA或吡啶持續合適時間量，諸如持續約10分鐘至約隔夜。其他適合條件包括添加DMAP。在一些實施例中，Y含有經保護之醇。在一些實施例中，Y受矽烷基醚保護。在一些實施例中，使用適合脫保護條件，包括合適溶劑、溫度及時間來移除保護基以產生游離醇，產生V - 10 。在一些實施例中，適合之脫保護條件包括使用HCl水溶液。在一些實施例中，合適溶劑為水、THF、甲醇或各溶劑之組合。在一些實施例中，合適溫度下之合適時間為在約0℃至約室溫下約30分鐘至約1小時。 在一些實施例中，使硼試劑V - 6 與雜芳基鹵化物V - 7 在適合的經金屬催化之交叉偶合反應條件下反應，得到V - 8 。在一些實施例中，雜芳基鹵化物為雜芳基溴化物或雜芳基碘化物。在一些實施例中，雜芳基鹵化物為吡唑基鹵化物。在一些實施例中，適合的經金屬催化之交叉偶合條件包括鈀。在一些實施例中，適合的經鈀催化之交叉偶合反應條件包括Pd(dppf)Cl2 及合適鹼及合適溶劑持續合適時間且處於合適溫度下。在一些實施例中，鹼為無機鹼。在一些實施例中，無機鹼為碳酸鹽鹼，諸如Na2 CO3 。在一些實施例中，合適溶劑為二噁烷、乙醇及水之混合物。在一些實施例中，合適時間及合適溫度為約隔夜，在約80℃下。在一些實施例中，使V - 8 經歷適合之硝基還原條件，得到苯胺V - 3 。適合之硝基還原條件包括經鈀催化之氫化條件。在一些實施例中，適合的經鈀催化之氫化條件包括在合適溫度下在適合溶劑，諸如甲醇中使用10% Pd/C及氫氣(1 atm)持續合適時間量。在一些實施例中，合適條件包括添加HCl水溶液。在一些實施例中，合適溫度下之合適時間量為在約室溫下約一小時。 在一些實施例中，如流程6中所概述製備本文所述之化合物。流程 6
Figure 02_image223
在流程6中，取代基X1 、X2 、X3 、X4 、R1 、R2 、R4 、R5 、R6 、R8 、R12 及m係如本文所述。在一些實施例中，X2 為C-R2 ，X3 為C-H且各X4 為C-H。 在一些實施例中，在適合溫度下由用R12 X對VI - 1 之鄰烷基化、適合鹼及適合溶劑，諸如THF製備化合物VI - 2 持續適合時間量。在一些實施例中，X為鹵化物。在一些實施例中，適合鹼為NaH。在一些實施例中，在合適溫度下，諸如在約0℃下用適合鹼預處理化合物VI - 1 持續適合時間量，諸如約0.5小時，之後添加鹵化物R12 X。在一些實施例中，合適時間及溫度為約隔夜，在約60℃下。 在一些實施例中，如流程7中所概述製備本文所述之化合物。流程 7
Figure 02_image225
在流程7中，取代基X1 、X2 、X3 、X4 、R1 、R2 、R4 、R5 、R6 、R8 及m係如本文所述。在一些實施例中，X2 為C-R2 ，X3 為C-H且各X4 為C-H。 在一些實施例中，使VII - 1 處於合適酸性條件下，得到胺VII - 2 。在一些實施例中，合適酸性條件包括在合適溫度下在適合溶劑，諸如DCM中使用TFA持續合適時間量。在一些實施例中，合適酸性條件包括在合適溫度下在適合溶劑，諸如二噁烷中使用HCl持續合適時間量。在一些實施例中，針對合適時間量之合適溫度為約0℃至約室溫，持續約0.5小時至約2小時。 在一些實施例中，如流程8中所概述製備用於製備本文所述之化合物的中間物。流程 8
Figure 02_image227
在流程8中，取代基X2 、X3 、X4 、R1 及R2 係如本文所述。在一些實施例中，X2 為C-R2 ，X3 為C-H且各X4 為C-H。在一些實施例中，X為鹵化物。在一些實施例中，X為氯、溴或碘。 在一些實施例中，將VIII - 1 冷卻至適合溫度，在適合金屬-鹵素交換條件下且在合適溫度下與合適溶劑反應持續合適時間，且隨後與合適酮VIII - 2 反應持續合適時間且在合適溫度下反應，得到三級醇。在一些實施例中，適合金屬-鹵素交換條件包括有機金屬試劑。在一些實施例中，合適溶劑為THF。在一些實施例中，有機金屬試劑為烷基鋰。在一些實施例中，烷基鋰為正丁基鋰。在一些實施例中，將VIII - 1 冷卻至約-78℃，之後添加有機金屬試劑。在一些實施例中，在約-78℃下使VIII - 1 反應持續約一小時，之後添加合適酮VIII - 2 。在一些實施例中，使VIII - 1 反應持續約2小時，之後添加酮VIII - 2 。在一些實施例中，VIII - 1 與酮VIII - 2 反應之合適溫度為約-78℃。在一些實施例中，在合適溶劑中且在合適溫度下使三級醇在合適烯丙基化條件下反應持續合適時間以形成VIII - 3 ，該等條件包括使用烯丙基化試劑及路易斯酸(Lewis acid)。在一些實施例中，合適烯丙基化試劑為烯丙基三甲基矽烷。在一些實施例中，合適路易斯酸為BF3 -OEt2 。在一些實施例中，合適溶劑為DCM。在一些實施例中，針對合適時間之合適溫度為約-78℃持續約1小時。在一些實施例中，將反應進一步升溫至約室溫持續約隔夜。在一些實施例中，針對合適時間之合適溫度為約0℃持續約隔夜。 在一些實施例中，使VIII - 3 在適合氧化裂解條件下在合適溶劑中且在合適溫度下反應持續合適時段以產生VIII - 4 。在一些實施例中，氧化裂解條件包括使用鋨試劑及N-甲基嗎啉N-氧化物以形成中間二醇。在一些實施例中，鋨試劑為OsO4 或K2 OsO4 -2H2 O。在一些實施例中，合適溶劑為ACN/水混合物。在一些實施例中，針對合適時間之合適溫度為約0℃至約室溫持續約隔夜。在一些實施例中，二醇在合適氧化裂解條件下在合適溶劑中且在合適溫度下斷裂持續合適時段以形成VIII - 4 。在一些實施例中，合適氧化裂解條件包括使用NaIO4 。在一些實施例中，合適溶劑為THF/水混合物。在一些實施例中，針對合適時間之合適溫度為約0℃至約室溫持續約隔夜。 在一些實施例中，使VIII - 4 在適合還原條件下還原成一級醇，且隨後在適合鹵化條件下鹵化以產生VIII - 5 。在一些實施例中，適合還原條件包括使用硼氫化物試劑。在一些實施例中，還原條件包括在合適溫度下在合適溶劑中使用NaBH4 持續合適時間量。在一些實施例中，合適溶劑為THF。在一些實施例中，針對合適時間之合適溫度為約0℃持續約一小時。在一些實施例中，將反應升溫至約室溫持續約隔夜。在一些實施例中，使醇在適合鹵化條件下反應以產生烷基鹵化物。在一些實施例中，適合鹵化條件為溴化條件，其包括在合適初始溫度下在合適溶劑中使用CBr4 ，之後在合適溫度下在合適溶劑中使用PPh3 持續合適時間。在一些實施例中，合適溶劑為鹵化溶劑，諸如DCM。在一些實施例中，合適初始溫度為約0℃。在一些實施例中，添加PPh3 之後的合適溫度及時間為約0℃持續約一小時。在一些實施例中，針對添加PPh3 之合適溶劑為THF。在一些實施例中，將反應進一步升溫至約室溫持續約隔夜。 在一些實施例中，使VIII - 5 經歷分子內烷基化條件以形成VIII - 6 。在一些實施例中，分子內烷基化條件包括適合鹼。在一些實施例中，適合鹼為二異丙胺基鋰，其在合適溫度下處於合適溶劑中持續合適時間量。在一些實施例中，合適溶劑為HMPA及THF混合物。在一些實施例中，針對合適時間量之合適溫度為約-78℃持續約3小時或約-78℃至室溫持續約隔夜。 在一些實施例中，藉由適合還原條件將VIII - 6 還原為醇，之後藉由適合氧化條件氧化為醛VIII - 7 。在一些實施例中，適合還原條件包括在合適溫度下在合適溶劑中使用DIBALH持續合適時間。在一些實施例中，合適溶劑為DCM。在一些實施例中，針對合適時間之合適溫度為約-78℃持續約一小時。在一些實施例中，將反應進一步升溫至約室溫持續約兩小時以產生醇。在一些實施例中，適合氧化條件為基於鉻之氧化。在一些實施例中，適合氧化條件包括在合適溫度下在合適溶劑中使用PCC持續合適時間。在一些實施例中，添加矽膠。在一些實施例中，合適溶劑為DCM。在一些實施例中，合適溫度為約室溫持續約2小時。或者在一些實施例中，氧化條件包括在合適溫度下在合適溶劑中使用乙二醯氯及DMSO以及胺鹼持續合適時間。在一些實施例中，合適胺鹼為TEA。在一些實施例中，合適溶劑為DCM。在一些實施例中，針對合適時間量之合適溫度為約-78℃持續約一小時。 在一些實施例中，如流程9中所概述製備用於製備本文所述之化合物的中間物。流程 9
Figure 02_image229
在一些實施例中，使IX - 1 經歷醇保護條件以形成雙矽烷基中間物，之後經歷水解條件以形成IX - 2 。在一些實施例中，醇保護條件包括在合適溫度下在合適溶劑中使用TBSCl及合適鹼且持續合適時段。在一些實施例中，合適溶劑為DMF。在一些實施例中，合適鹼為咪唑。在一些實施例中，針對合適時間之合適溫度為約室溫持續約2小時。在一些實施例中，使中間物矽烷基酯經歷水解條件以形成IX - 2 。在一些實施例中，水解條件包括在合適溫度下在合適溶劑中用鹼處理且持續合適時段。在一些實施例中，合適溶劑為EtOH、H2 O、THF混合物。在一些實施例中，合適鹼為K2 CO3 。在一些實施例中，針對合適時間之合適溫度為約室溫持續約3小時。 在一些實施例中，在氯化條件下將化合物IX - 2 轉化成酸氯化物IX - 3 。在一些實施例中，氯化條件包括在適合溫度下在適合溶劑中使用(氯亞甲基)二甲基氯化亞銨((chloromethylene)dimethyliminium chloride)及鹼。在一些實施例中，適合鹼為無水K2 CO3 。在一些實施例中，適合溫度為約0℃。在一些實施例中，適合溶劑為甲苯。在一些實施例中，添加IX - 2 且在適合溫度下攪拌混合物持續適合時間以產生IX - 3 。在一些實施例中，針對適合時間之適合溫度為約室溫持續約0.5至約一小時。 在一些實施例中，如流程10中所概述製備本文所述之化合物。流程 10
Figure 02_image231
在流程10中，取代基Y、X1 、X2 、X3 、X4 、R1 、R2 、R6 、R8 及m係如本文所述。在一些實施例中，X2 為C-R2 ，X3 為C-H且各X4 為C-H。 在一些實施例中，使醇X - 1 在適合鹵化條件下反應以產生烷基鹵化物X - 2 。在一些實施例中，適合鹵化條件為溴化條件，其包括在合適初始溫度下在合適溶劑中使用CBr4 ，之後在合適溫度下在合適溶劑中使用PPh3 持續合適時間。在一些實施例中，合適溶劑為鹵化溶劑，諸如DCM。在一些實施例中，合適初始溫度為約0℃。在一些實施例中，添加PPh3 之後的合適溫度及時間為約0℃持續約一小時。在一些實施例中，將反應進一步升溫至約室溫持續約隔夜。 在一些實施例中，用醯氯醯化胺X - 3 ，得到化合物X - 4 。適合醯化條件包括(但不限於)在適合溫度，諸如約0℃下在適合溶劑，諸如DCM或甲苯中使用適合鹼，諸如吡啶。在一些實施例中，在合適溫度下在合適溶劑中添加醯氯持續合適時間量。在一些實施例中，合適溶劑為甲苯。在一些實施例中，合適溫度為約0℃，隨後升溫至室溫持續約隔夜。在一些實施例中，在適合溫度下在適合溶劑，諸如DMF中由用溴化物X - 2 對X - 4 之N-烷基化及適合鹼製備化合物X - 5 持續適合時間量。適合鹼包括NaH。在一些實施例中，在合適溫度下，諸如在約0℃至約室溫下用適合鹼預處理化合物X - 4 持續適合時間量，諸如約兩小時，之後添加溴化物X - 2 。在一些實施例中，添加溴化物X - 2 之後的合適時間及溫度為約室溫持續約隔夜。在一些實施例中，Y含有經保護之醇。在一些實施例中，Y受矽烷基醚保護。在一些實施例中，使用適合脫保護條件，包括合適溶劑、溫度及時間來移除保護基以產生游離醇，產生X - 5 。在一些實施例中，適合脫保護條件包括使用氟化物試劑。在一些實施例中，氟化物試劑為NH4 F。在一些實施例中，合適溶劑為甲醇。在一些實施例中，合適溫度下之合適時間為約隔夜，在約60℃下。 在一些實施例中，如流程11中所概述製備本文所述之化合物。流程 11
Figure 02_image233
在流程11中，取代基Y、X1 、X2 、X3 、X4 、R1 、R2 、R4 、R5 、R6 、R8 及m係如本文所述。在一些實施例中，X2 為C-R2 ，X3 為C-H且各X4 為C-H。在一些實施例中，X為適合交叉偶合取代基。在一些實施例中，X為鹵化物。在一些實施例中，X為氯、溴或碘。 在一些實施例中，使化合物XI - 1 與適合乙炔源在適合的經金屬催化之交叉偶合反應條件下反應，得到XI - 2 。在一些實施例中，適合的經金屬催化之交叉偶合條件包括鈀。在一些實施例中，適合乙炔源為三甲基矽烷基乙炔。在一些實施例中，適合的經鈀催化之交叉偶合反應條件包括Pd(PPh3 )2 Cl2 、銅催化劑及合適鹼持續合適時間且在合適溫度下。在一些實施例中，銅催化劑為CuI。在一些實施例中，鹼為胺鹼，諸如TEA。在一些實施例中，合適時間及合適溫度為約6小時，在約90℃下。在一些實施例中，在交叉偶合之後，在適合脫保護條件下移除TMS基團以形成XI - 2 ，該等條件包括合適溶劑、溫度及時間。在一些實施例中，適合脫保護條件包括使用氟化物試劑。在一些實施例中，氟化物試劑為NH4 F。在一些實施例中，合適溶劑為甲醇。在一些實施例中，約60℃下之合適時間為約一小時。 在一些實施例中，使乙炔XI - 2 與適合雜芳族鹵化物在適合的經金屬催化之交叉偶合反應條件下反應，得到XI - 3 。在一些實施例中，適合的經金屬催化之交叉偶合條件包括鈀。在一些實施例中，適合雜芳族鹵化物為吡唑基鹵化物。在一些實施例中，雜芳族鹵化物為雜芳族碘化物。在一些實施例中，適合的經鈀催化之交叉偶合反應條件包括Pd(PPh3 )2 Cl2 、銅催化劑及合適鹼持續合適時間且在合適溫度下。在一些實施例中，銅催化劑為CuI。在一些實施例中，鹼為胺鹼，諸如TEA。在一些實施例中，合適時間及合適溫度為約一小時，在約80℃至約90℃或約70℃至約90℃下。 在一些實施例中，Y含有經保護之醇。在一些實施例中，Y受矽烷基醚保護。在一些實施例中，使用適合脫保護條件，包括合適溶劑、溫度及時間來移除保護基以產生游離醇，產生XI - 3 。在一些實施例中，適合之脫保護條件包括使用HCl水溶液。在一些實施例中，合適溶劑為水、THF、甲醇或各溶劑之組合。在一些實施例中，合適溫度下之合適時間為在約0℃至約室溫下約30分鐘至約1小時。 在一些實施例中，如實例中所述製備化合物。特定術語 除非另外說明，否則本申請案中所用之以下術語具有下文給定之定義。術語「包括(including)」以及其他形式，諸如「包括(include)」、「包括(includes)」及「包括(included)」之使用不具限制性。本文中所用之章節標題僅出於組織目的而不應理解為限制所述標的物。 如本文所用，C1 -Cx 包括C1 -C2 、C1 -C3 ……C1 -Cx 。僅舉例而言，表示為「C1 -C4 」之基團指示部分中存在一至四個碳原子，亦即含有1個碳原子、2個碳原子、3個碳原子或4個碳原子之基團。因此，僅舉例而言，「C1 -C4 烷基」指示烷基中存在一至四個碳原子，亦即烷基係選自以下之中：甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基及第三丁基。 「烷基」係指脂族烴基。烷基為分支鏈或直鏈。在一些實施例中，「烷基」具有1至10個碳原子，亦即C1 -C10 烷基。不論何時出現在本文中時、諸如「1至10」之數值範圍係指所給範圍內之各整數；例如，「1至10個碳原子」意謂該烷基由1個碳原子、2個碳原子、3個碳原子、4個碳原子、5個碳原子、6個碳原子等組成，至多(且包括)10個碳原子，但本發明定義亦涵蓋其中沒有指定數值範圍之術語「烷基」的存在。在一些實施例中，烷基為C1 -C6 烷基。在一個態樣中，烷基為甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基。典型烷基包括(但不限於)甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、新戊基或己基。 「伸烷基」係指二價烷基。以上提及之單價烷基中之任一者藉由自烷基提取第二氫原子可為伸烷基。在一些實施例中，伸烷基為C1 -C6 伸烷基。在其他實施例中，伸烷基為C1 -C4 伸烷基。在某些實施例中，伸烷基包含一至四個碳原子(例如C1 -C4 伸烷基)。在其他實施例中，伸烷基包含1至3個碳原子(例如C1 -C3 伸烷基)。在其他實施例中，伸烷基包含一至兩個碳原子(例如C1 -C2 伸烷基)。在其他實施例中，伸烷基包含一個碳原子(例如C1 伸烷基)。在其他實施例中，伸烷基包含兩個碳原子(例如C2 伸烷基)。在其他實施例中，伸烷基包含兩至四個碳原子(例如C2 -C4 伸烷基)。典型伸烷基包括(但不限於)-CH2 -、-CH(CH3 )-、-C(CH3 )2 -、-CH2 CH2 -、-CH2 CH(CH3 )-、-CH2 C(CH3 )2 -、-CH2 CH2 CH2 -、-CH2 CH2 CH2 CH2 -及其類似者。 「氘代烷基」係指其中烷基之1或多個氫原子經氘替代之烷基。 術語「烯基」係指其中存在至少一個碳碳雙鍵之烷基類型。在一個實施例中，烯基具有式 -C(R)=CR2 ，其中R係指烯基之其餘部分，其可以相同或不同。在一些實施例中，R為H或烷基。在一些實施例中，烯基係選自乙烯基(ethenyl) (亦即乙烯基(vinyl))、丙烯基(亦即烯丙基)、丁烯基、戊烯基、戊二烯基及其類似者。烯基之非限制性實例包括-CH=CH2 、-C(CH3 )=CH2 、-CH=CHCH3 、-C(CH3 )=CHCH3 及-CH2 CH=CH2 。 術語「炔基」係指其中存在至少一個碳-碳參鍵之烷基類型。在一個實施例中，炔基具有式-C≡C-R，其中R係指炔基之其餘部分。在一些實施例中，R為H或烷基。在一些實施例中，炔基係選自乙炔基、丙炔基、丁炔基、戊炔基、己炔基及其類似者。炔基之非限制性實例包括-C≡CH、-C≡CCH3 、-C≡CCH2 CH3 、-CH2 C≡CH。 「烷氧基」係指(烷基)O-基團，其中烷基係如本文中所定義。 術語「烷基胺」係指-N(烷基)x Hy 基團，其中x為0且y為2，或其中x為1且y為1，或其中x為2且y為0。 術語「芳族」係指具有非定域π電子系統之平面環，該系統含有4n+2π個電子，其中n為整數。術語「芳族」包括碳環芳基(「芳基」，例如苯基)及雜環芳基(或「雜芳基」或「雜芳族」)(例如吡啶)兩者。該術語包括單環或稠環多環(亦即，共用相鄰碳原子或氮原子對之環)基團。 術語「碳環(carbocyclic)」或「碳環(carbocycle)」係指形成環主鏈之原子為所有碳原子之環或環系統。該術語由此將碳環與其中環主鏈含有至少一個與碳不同之原子的「雜環」環或「雜環」區分開。在一些實施例中，雙環碳環之兩個環中之至少一者為芳族的。在一些實施例中，雙環碳環之兩個環均為芳族的。碳環包括環烷基及芳基。 如本文所用，術語「芳基」係指形成環之原子中之每一者為碳原子之芳環。在一個態樣中，芳基為苯基或萘基。在一些實施例中，芳基為苯基。在一些實施例中，芳基為C6 -C10 芳基。視結構而定，芳基為單自由基或雙自由基(亦即伸芳基)。 術語「環烷基」係指單環或多環脂族、非芳族自由基，其中形成環的原子(亦即骨架原子)中之每一者為碳原子。在一些實施例中，環烷基為螺環或橋連化合物。在一些實施例中，環烷基視情況與芳環稠合，且連接點處於並非芳環碳原子之碳處。環烷基包括具有3至10個環原子之基團。在一些實施例中，環烷基係選自以下之中：環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基、環辛基、螺[2.2]戊基、降𦯉基及雙環[1.1.1]戊基。在一些實施例中，環烷基為C3 -C6 環烷基。在一些實施例中，環烷基為單環環烷基。單環環烷基包括(但不限於)環丙基、環丁基、環戊基、環己基、環庚基及環辛基。多環環烷基包括例如金剛烷基、降𦯉基(亦即雙環[2.2.1]庚基)、降𦯉烯基、十氫萘基、7,7-二甲基-雙環[2.2.1]庚基及其類似者。 術語「鹵基」，或替代地，「鹵素」或「鹵化物」意謂氟、氯、溴或碘。在一些實施例中，鹵基為氟、氯或溴。 術語「鹵烷基」係指一或多個氫原子由鹵素原子置換之烷基。在一個態樣中，氟烷基為C1 -C6 氟烷基。 術語「氟烷基」係指一或多個氫原子由氟原子置換之烷基。在一個態樣中，氟烷基為C1 -C6 氟烷基。在一些實施例中，氟烷基係選自三氟甲基、二氟甲基、氟甲基、2,2,2-三氟乙基、1-氟甲基-2-氟乙基及其類似者。 術語「雜烷基」係指烷基之一或多個骨架原子係選自除碳外之原子，例如氧、氮(例如-NH-、-N(烷基)-)、硫或其組合的烷基。雜烷基在雜烷基之碳原子處附接於分子之其餘部分。在一個態樣中，雜烷基為C1 -C6 雜烷基。 術語「雜環(heterocycle)」或「雜環(heterocyclic)」係指在環中含有一至四個雜原子之雜芳族環(亦稱為雜芳基)及雜環烷基環(亦稱為雜脂環基團)，其中環中之各雜原子係選自O、S及N，其中各雜環基在其環系統中具有3至10個原子，且其限制條件為任何環不含兩個相鄰O或S原子。在一些實施例中，雜環為單環、雙環、多環、螺環或橋連化合物。非芳族雜環基(亦稱為雜環烷基)包括在其環系統中具有3至10個原子之環，且芳族雜環基包括在其環系統中具有5至10個原子之環。雜環基包括苯并稠合環系統。非芳族雜環基之實例為吡咯啶基、四氫呋喃基、二氫呋喃基、四氫噻吩基、噁唑啶酮基、四氫哌喃基、二氫哌喃基、四氫硫代哌喃基、哌啶基、嗎啉基、硫代嗎啉基、硫氧雜環己烷基、哌嗪基、氮丙啶基、氮雜環丁烷基、氧雜環丁烷基、硫雜環丁烷基、高哌啶基、氧雜環庚烷基、硫雜環庚基、噁氮呯基、二氮呯基、噻環氮己三烯基(thiazepinyl)、1,2,3,6-四氫吡啶基、吡咯啉-2-基、吡咯啉-3-基、吲哚啉基、2H-哌喃基、4H-哌喃基、二氧雜環己烷基、1,3-二氧戊環基、吡唑啉基、二噻烷基、二硫㖦基、二氫哌喃基、二氫噻吩基、二氫呋喃基、吡唑啶基、咪唑啉基、咪唑啶基、3-氮雜雙環[3.1.0]己基、3-氮雜雙環[4.1.0]庚基、3H-吲哚基、吲哚啉-2-酮基、異吲哚啉-1-酮基、異吲哚啉-1,3-二酮基、3,4-二氫異喹啉-1(2H)-酮基、3,4-二氫喹啉-2(1H)-酮基、異吲哚啉-1,3-二亞硫醯基、苯并[d]噁唑-2(3H)-酮基、1H-苯并[d]咪唑-2(3H)-酮基、苯并[d]噻唑-2(3H)-酮基及喹嗪基。芳族雜環基之實例為吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、異噁唑基、噻唑基、噁唑基、異噻唑基、吡咯基、喹啉基、異喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、㖕啉基、吲唑基、吲哚嗪基、酞嗪基、噠嗪基、三嗪基、異吲哚基、喋啶基、嘌呤基、噁二唑基、噻二唑基、呋呫基、苯并呋呫基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喏啉基、㖠啶基及呋喃并吡啶基。前述基團為C-連接(或C-鍵聯的)或N - 連接的(在可能之情況下)。舉例而言，衍生自吡咯之基團包括吡咯-1-基(N -連接)或吡咯-3-基(C-連接)兩者。雜環基包括苯并稠合環系統。非芳族雜環視情況經一或兩個側氧基(=O)部分取代，諸如吡咯啶-2-酮。在一些實施例中，雙環雜環之兩個環中之至少一者為芳族的。在一些實施例中，雙環雜環之兩個環均為芳族的。 術語「雜芳基」，或替代地，「雜芳族」係指包括一或多個選自氮、氧及硫之環雜原子之芳基。雜芳基之說明性實例包括單環雜芳基及雙環雜芳基。單環雜芳基包括吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、異噁唑基、噻唑基、噁唑基、異噻唑基、吡咯基、噠嗪基、三嗪基、噁二唑基、噻二唑基及呋呫基。雙環雜芳基包括吲哚嗪、吲哚、苯并呋喃、苯并噻吩、吲唑、苯并咪唑、嘌呤、喹嗪、喹啉、異喹啉、㖕啉、酞嗪、喹唑啉、喹喏啉、1,8-㖠啶及喋啶。在一些實施例中，雜芳基在環中含有0至4個N原子。在一些實施例中，雜芳基在環中含有1至4個N原子。在一些實施例中，雜芳基在環中含有0至4個N原子、0至1個O原子及0至1個S原子。在一些實施例中，雜芳基在環中含有1至4個N原子、0至1個O原子及0至1個S原子。在一些實施例中，雜芳基為C1 -C9 雜芳基。在一些實施例中，單環雜芳基為C1 -C5 雜芳基。在一些實施例中，單環雜芳基為5員或6員雜芳基。在一些實施例中，雙環雜芳基為C6 -C9 雜芳基。 「雜環烷基」或「雜脂環」基團係指包括至少一個選自氮、氧及硫之雜原子的環烷基。在一些實施例中，雜環烷基與芳基或雜芳基稠合。在一些實施例中，雜環烷基為噁唑啶酮基、吡咯啶基、四氫呋喃基、四氫噻吩基、四氫哌喃基、四氫硫代哌喃基、哌啶基、嗎啉基、硫代嗎啉基、哌嗪基、哌啶-2-酮基、吡咯啶-2,5-二亞硫醯基、吡咯啶-2,5-二酮基、吡咯啶酮基、咪唑啶基、咪唑啶-2-酮基或噻唑啶-2-酮基。術語雜脂環亦包括碳水化合物之所有環形式，其包括(但不限於)單醣、雙醣及寡醣。在一個態樣中，雜環烷基為C2 -C10 雜環烷基。在一個態樣中，雜環烷基為C4 -C10 雜環烷基。在一些實施例中，雜環烷基在環中含有0至2個N原子。在一些實施例中，雜環烷基在環中含有0至2個N原子、0至2個O原子及0至1個S原子。 術語「鍵」或「單鍵」係指當藉由鍵連接之原子視為較大子結構之一部分時，兩個原子或兩個部分之間的化學鍵。在一個態樣中，當本文所述之基團為一鍵時，所提及之基團不存在，由此使得其餘已確定基團之間形成一鍵。 術語「部分」係指分子之特定區段或官能基。化學部分為嵌入或附接至分子之通常公認之化學實體。 術語「視情況經取代」或「經取代」意謂所提及之基團視情況經一或多個其他基團取代，該(等)基團單獨地且獨立地選自D、鹵素、-CN、-NH2 、-NH(烷基)、-N(烷基)2 、-OH、-CO2 H、-CO2 烷基、-C(=O)NH2 、-C(=O)NH(烷基)、-C(=O)N(烷基)2 、-S(=O)2 NH2 、-S(=O)2 NH(烷基)、-S(=O)2 N(烷基)2 、烷基、烯基、炔基、環烷基、氟烷基、雜烷基、烷氧基、氟烷氧基、雜環烷基、芳基、雜芳基、芳氧基、烷硫基、芳硫基、烷基亞碸、芳基亞碸、烷基碸及芳基碸。在一些其他實施例中，視情況選用之取代基獨立地選自D、鹵素、-CN、-NH2 、-NH(CH3 )、-N(CH3 )2 、-OH、-CO2 H、-CO2 (C1 -C4 烷基)、-C(=O)NH2 、-C(=O)NH(C1 -C4 烷基)、-C(=O)N(C1 -C4 烷基)2 、-S(=O)2 NH2 、-S(=O)2 NH(C1 -C4 烷基)、-S(=O)2 N(C1 -C4 烷基)2 、C1 -C4 烷基、C3 -C6 環烷基、C1 -C4 氟烷基、C1 -C4 雜烷基、C1 -C4 烷氧基、C1 -C4 氟烷氧基、-SC1 -C4 烷基、-S(=O)C1 -C4 烷基及-S(=O)2 C1 -C4 烷基。在一些實施例中，視情況選用之取代基獨立地選自D、鹵素、-CN、-NH2 、-OH、-NH(CH3 )、-N(CH3 )2 、-CH3 、-CH2 CH3 、-CF3 、-OCH3 及-OCF3 。在一些實施例中，經取代之基團經先前基團中之一或兩者取代。在一些實施例中，脂族碳原子(非環狀或環狀)上的視情況選用之取代基包括側氧基(=O)。 如本文所用之關於調配物、組合物或成分之術語「可接受」意謂對所治療之個體的整體健康不具有持續有害作用。 如本文中所用，術語「調節」意謂與標靶直接或間接相互作用以便改變標靶之活性，包括僅舉例而言，增強標靶之活性、抑制標靶之活性、限制標靶之活性或延伸標靶之活性。 如本文所用，術語「調節劑」係指與標靶直接或間接相互作用之分子。相互作用包括(但不限於)促效劑、部分促效劑、反向促效劑、拮抗劑、下調劑或其組合之相互作用。在一些實施例中，調節劑為促效劑。 如本文所用，術語「投與(administer)」、「投與(administering)」、「投與(administration)」及其類似術語係指可用於實現將化合物或組合物遞送至所需生物作用位點的方法。此等方法包括(但不限於)經口途徑、十二指腸內途徑、非經腸注射(包括靜脈內、皮下、腹膜內、肌肉內、血管內或輸注)、表面及經直腸投藥。熟習此項技術者熟悉本文中所述之化合物及方法可採用之投與技術。在一些實施例中，本文中所述之化合物及組合物為經口投與。 如本文所用，術語「共投與」或其類似術語意謂涵蓋向單個患者投與所選治療劑，且意欲包括以相同或不同投與途徑或同時或不同時投與藥劑之治療方案。 如本文所用，術語「有效量」或「治療有效量」係指足以在一定程度上減輕所治療之疾病或病狀之一或多種症狀的所投與之藥劑或化合物之量。結果包括減輕及/或緩解疾病之病徵、症狀或病因，或生物系統之任何其他所需改變。舉例而言，用於治療用途之「有效量」為使疾病症狀臨床上顯著減少所需之包含如本文所揭示之化合物之組合物的量。使用諸如劑量遞增研究之技術來視情況測定任何個別情況下之適當「有效」量。 如本文所用，術語「增強(enhance/enhancing)」意謂增加或延長所需效應之效能或持續時間。因此，關於增強治療劑之作用，術語「增強」係指增加或延長其他治療劑對系統之作用的效能或持續時間之能力。如本文所用，「增強有效量」係指足以增強其他治療劑在所需系統中之作用的量。 如本文所用，術語「醫藥組合」意謂由混合或組合超過一種活性成分所產生之產物且包括活性成分之固定與不固定組合。術語「固定組合」意謂活性成分，例如本文所述之化合物或其醫藥學上可接受之鹽及助劑均以單一實體或劑量形式同時向患者投與。術語「非固定組合」意謂活性成分，例如本文所述之化合物或其醫藥學上可接受之鹽及助劑以分離實體形式同時、並行或依序向患者投與而無特定介入時間限制，其中此類投藥在患者體內提供有效含量之兩種化合物。後者亦適用於混合物療法，例如投與三種或大於三種活性成分。 術語「套組」及「製品」以同義語形式使用。 術語「個體」或「患者」涵蓋哺乳動物。哺乳動物之實例包括(但不限於)哺乳動物類別的任何成員：人類、非人類靈長類(諸如黑猩猩及其他猿類及猴類物種)；農畜，諸如牛、馬、綿羊、山羊、豬；家畜，諸如兔、狗及貓；實驗室動物，包括嚙齒動物，諸如大鼠、小鼠及天竺鼠以及其類似動物。在一個態樣中，哺乳動物為人類。 如本文所用，術語「治療(treat/treating/treatment)」包括預防性及/或治療性地緩解、緩和或改善疾病或病狀之至少一種症狀；預防其他症狀；抑制疾病或病狀，例如使疾病或病狀之發展停滯；減輕疾病或病狀；致使疾病或病狀消退；減輕疾病或病狀所導致之病狀；或使疾病或病狀之症狀停止。醫藥組合物 在一些實施例中，將本文所述之化合物調配成醫藥組合物。醫藥組合物以習知方式使用一或多種有助於加工活性化合物之醫藥學上可接受之非活性成分調配成醫藥學上所用之製劑。適當調配物視所選擇之投與途徑而定。本文所述之醫藥組合物之概述見於例如Remington: The Science and Practice of Pharmacy, 第19版 (Easton, Pa.: Mack Publishing Company, 1995)；Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975；Liberman, H.A.及Lachman, L.編, Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980；及Pharmaceutical Dosage Forms and Drug Delivery Systems, 第七版 (Lippincott Williams & Wilkins1999)，關於此類揭示內容，以引用之方式併入本文中。 在一些實施例中，單獨或以醫藥組合物形式與醫藥學上可接受之載劑、賦形劑或稀釋劑組合投與本文所述之化合物。本文所述之化合物及組合物之投與可藉由使得化合物能夠遞送至作用位點之任何方法來實現。此等方法包括(但不限於)經由以下進行遞送：經腸途徑(包括口服、胃或十二指腸飼管、直腸栓劑及直腸灌腸劑)、非經腸途徑(注射或輸注，包括動脈內、心內、皮內、十二指腸內、髓內、肌肉內、骨內、腹膜內、鞘內、血管內、靜脈內、玻璃體內、硬膜外及皮下)、吸入、經皮、經黏膜、舌下、經頰及表面(包括上表皮、真皮、灌腸、滴眼劑、滴耳劑、鼻內、陰道)投與，但最適合途徑可視例如接受者之病狀及病症而定。僅舉例而言，本文所述之化合物可例如藉由在手術期間局部輸注、局部施用諸如乳膏或軟膏、注射、導管或植入表面投與至需要治療之區域。亦可藉由在患病組織或器官之位點處直接注射來進行投藥。 在一些實施例中，適用於口服之醫藥組合物以離散單位形式呈現，諸如膠囊、扁囊劑或錠劑，各含有預定量之活性成分；呈粉末或顆粒形式；呈水性液體或非水性液體中之溶液或懸浮液形式；或呈水包油液體乳液或油包水液體乳液形式。在一些實施例中，活性成分以大丸劑、舐劑或糊劑形式呈現。 可口服使用之醫藥組合物包括錠劑、由明膠製成之配合插入型膠囊(push-fit capsule)以及由明膠及塑化劑,諸如甘油或山梨糖醇製成之軟密封膠囊。錠劑可藉由視情況與一或多種附屬成分一起壓縮或模製來製造。壓縮錠劑可藉由在適合機器中壓縮呈自由流動形式(諸如粉末或顆粒)之視情況與黏合劑、惰性稀釋劑或潤滑劑、表面活性劑或分散劑混合的活性成分來製備。成型錠劑可藉由使經惰性液體稀釋劑濕潤之粉末狀化合物之混合物在適合機器中成型來製造。在一些實施例中，錠劑經塗佈或刻痕且經調配以便提供其中活性成分之緩慢或控制釋放。用於口服之所有調配物均應呈適於此類投與之劑量。配合插入型膠囊可含有活性成分與諸如乳糖之填充劑、諸如澱粉之黏合劑及/或諸如滑石或硬脂酸鎂之潤滑劑以及視情況選用之穩定劑的混合物。在軟膠囊中，活性化合物可溶解或懸浮於諸如脂肪油、液體石蠟或液體聚乙二醇之適合液體中。在一些實施例中，添加穩定劑。糖衣藥丸核心具有適合包衣。出於此目的，可使用濃縮糖溶液，其可視情況含有阿拉伯膠、滑石、聚乙烯基吡咯啶酮、卡波莫凝膠(carbopol gel)、聚乙二醇及/或二氧化鈦、漆液及適合有機溶劑或溶劑混合物。可向錠劑或糖衣藥丸包衣中添加染料或顏料來標識或表徵活性化合物劑量之不同組合。 在一些實施例中，醫藥組合物經調配而藉由注射，例如藉由快速注射或連續輸注進行非經腸投藥。注射用調配物可呈現為單位劑型，例如安瓿或多劑量容器，其中添加有防腐劑。組合物可採用諸如於油性或水性媒劑中之懸浮液、溶液或乳液之形式且可含有諸如懸浮劑、穩定劑及/或分散劑之調配劑。組合物可存在於例如密封之安瓿及小瓶之單位劑量或多劑量容器中，且在即將使用之前可以粉末形式或在僅需要添加無菌液體載劑(例如生理鹽水或無菌無熱原質之水)的冷凍乾燥(凍乾)條件下儲存。可由上述種類之無菌粉末、顆粒及錠劑製備即用型注射溶液及懸浮液。 用於非經腸投與之醫藥組合物包括可含有抗氧化劑、緩衝劑、抑菌劑及使調配物與預期接受者血液等張之溶質的水性及非水性(油性)無菌注射溶液；及可包括懸浮劑及增稠劑之水性及非水性無菌懸浮液。適合親脂性溶劑或媒劑包括脂肪油，諸如芝麻油；或合成脂肪酸酯，諸如油酸乙酯或三酸甘油酯；或脂質體。水性注射懸浮液可含有增加懸浮液黏度之物質，諸如羧甲基纖維素鈉、山梨糖醇或葡聚糖。視情況地，懸浮液亦可含有適合穩定劑或增加化合物溶解性之試劑以允許製備高度濃縮之溶液。 醫藥組合物亦可以儲槽式製劑(depot preparation)形式調配。此類長效調配物可藉由植入(例如皮下或肌肉內植入)或藉由肌肉內注射來投與。因此，化合物可例如用適合聚合或疏水性材料調配(例如調配成於可接受之油中的乳液)或用離子交換樹脂調配，或調配成微溶衍生物(例如微溶鹽)。 對於經頰或舌下投藥，組合物可採用以習知方式調配之錠劑、口含錠、片劑或凝膠形式。該等組合物可包含在可口基質(諸如蔗糖及阿拉伯膠或黃蓍膠)中之活性成分。 醫藥組合物亦可以諸如栓劑或保留灌腸劑之經直腸組合物形式調配，例如含有習知栓劑基質，諸如可可脂、聚乙二醇或其他甘油酯。 醫藥組合物可表面投與，亦即藉由非全身性投與。此包括將本發明化合物外部施用至表皮或頰腔，且將該種化合物滴入耳、眼及鼻中，以使得該化合物不顯著進入血流。相比而言，全身性投藥係指口服、靜脈內、腹膜內及肌肉內投藥。 適用於局部投與之醫藥組合物包括適用於穿透皮膚至發炎位點之液體或半液體製劑，諸如凝膠、搽劑、洗劑、乳膏、軟膏或糊劑及適用於投與至眼、耳或鼻中之滴劑。對於表面投藥而言，按調配物之重量計，活性成分可佔0.001% w/w至10% w/w，例如1% w/w至2% w/w。 用於藉由吸入投與之醫藥組合物宜藉由吹藥器、噴霧器加壓封裝或遞送氣溶膠噴霧之其他適宜方法來遞送。加壓封裝可包含適合之推進劑，諸如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他適合之氣體。在加壓氣溶膠之情況下，劑量單位可藉由提供遞送計量之量的閥來確定。或者，對於藉由吸入或吹入投藥而言，醫藥製劑可採用乾粉組合物形式，例如化合物與適合之粉末基質(諸如乳糖或澱粉)之粉末混合物。粉末組合物可以例如膠囊、藥筒、明膠或泡殼包裝之單位劑型呈現，粉末可藉助於吸入器或吹藥器自其投與。 在一些實施例中，以使得達成將化合物遞送至胃腸道之特定區域的方式來調配本文所揭示之化合物。舉例而言，本文所揭示之化合物調配用於與生物黏著聚合物、pH敏感塗層、時間相依性可生物降解之聚合物、微生物群活化系統及其類似者一起口服遞送，以便影響化合物遞送至胃腸道之特定區域。 在一些實施例中，本文所揭示之化合物經調配以使化合物控制釋放。控制釋放係指根據所需概況歷經較長時段將本文所述之化合物自併入其之劑型進行釋放。控制釋放型態包括例如持續釋放、延長釋放、脈衝釋放及延遲釋放型態。與立即釋放組合物相比，控制釋放組合物根據預定概況經較長時段將藥劑遞送至個體。與習知快速釋放劑型相比，此類釋放速率可在較長時段內提供治療有效含量之藥劑，且由此在使副作用降至最低的同時提供較長之藥物反應期。此類較長反應期提供許多固有益處，該等固有益處為相應短效作用、立即釋放製劑無法獲得的。將完整治療性化合物遞送至胃腸道之特定區域(例如結腸)的方法包括： (i) 用聚合物塗佈：完好分子可藉由用僅在結腸中降解之適合聚合物塗佈藥物分子而在不會吸收於腸之上部的情況下遞送至結腸。 (ii) 用pH敏感聚合物塗佈：腸及結腸靶向遞送系統之大部分係基於填充於習知硬明膠膠囊中之錠劑或丸粒。最常用之pH依從性包衣聚合物為甲基丙烯酸共聚物，通常已知為Eudragit® S，更具體言之，Eudragit® L及Eudragit® S。Eudragit® L100及S 100為甲基丙烯酸與甲基丙烯酸甲酯之共聚物。 (iii) 用可生物降解之聚合物塗佈； (iv) 包埋於基質中； (v) 包埋於可生物降解之基質及水凝膠中； (vi) 包埋於pH敏感性基質中； (vii) 定時釋放系統； (viii) 氧化還原敏感性聚合物； (ix) 生物黏著性系統； (x) 用微米粒子塗佈； (xi) 滲透控制藥物遞送； 針對結腸靶向藥物遞送或控制釋放系統之另一方法包括將藥物包埋於聚合物基質中以使其得到捕集且將其釋放於結腸中。此等基質可pH敏感性的或可生物降解的。基質類系統，諸如多基質(MMX)類延遲釋放錠劑會確保藥物釋放於結腸中。 將治療劑靶向遞送至胃腸道之特定區域的其他醫藥方法為已知的。Chourasia MK、Jain SK, Pharmaceutical approaches to colon targeted drug delivery systems., J Pharm Pharm Sci. 2003年一月至四月;6(1):33-66。Patel M、Shah T、Amin A. Therapeutic opportunities in colon-specific drug-delivery systems Crit Rev Ther Drug Carrier Syst. 2007;24(2):147-202。Kumar P、Mishra B. Colon targeted drug delivery systems--an overview. Curr Drug Deliv. 2008年七月;5(3):186-98。Van den Mooter G. Colon drug delivery. Expert Opin Drug Deliv. 2006年一月;3(1):111-25。Seth Amidon、Jack E. Brown及Vivek S. Dave, Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches, AAPS PharmSciTech. 2015年八月; 16(4): 731-741。 應瞭解，除以上特別提及之成分之外，本文所述之化合物及組合物還可包括考慮到所論述之調配物類型之此項技術中習知之其他試劑，例如彼等適用於經口投與之化合物及組合物可包括調味劑。給藥方法及治療方案 在一個實施例中，本文所述之化合物或其醫藥學上可接受之鹽用於製備用於治療將受益於FXR促效劑之投藥的哺乳動物中之疾病或病狀的藥劑。用於治療需要此類治療之哺乳動物中的本文所述之疾病或病狀中之任一者的方法涉及以治療有效量向該哺乳動物投與醫藥組合物，其包括至少一種本文所述之化合物或其醫藥學上可接受之鹽、活性代謝物、前藥或醫藥學上可接受之溶劑合物。 本文揭示投與FXR促效劑以及額外治療劑之方法。在一些實施例中，額外治療劑包含用於治療糖尿病或糖尿病相關病症或病狀、酒精性或非酒精性肝臟疾病、炎症相關腸道病狀或細胞增殖性病症之治療劑。 在某些實施例中，投與含有本文所述化合物之組合物以進行防治性及/或治療性治療。在某些治療應用中，將組合物以足以治癒或至少部分抑制疾病或病狀之至少一種症狀之量投與已患疾病或病狀之患者。對此用途有效之量視疾病或病狀之嚴重程度及病程、先前療法、患者之健康狀況、體重及對藥物之反應以及治療醫師之判斷而定。治療有效量視情況藉由包括(但不限於)劑量遞增及/或劑量範圍臨床試驗之方法來測定。 在預防性應用中，向易患特定疾病、病症或病狀或處於特定疾病、病症或病狀風險下之患者投與含有本文所述之化合物之組合物。此類量定義為「預防有效量或劑量」。在此用途中，精確量亦視患者之健康狀況、體重及其類似者而定。當用於患者中時，對此用途之有效量將視疾病、病症或病狀之嚴重程度及病程、先前療法、患者之健康狀況及對藥物之反應以及治療醫師之判斷而定。在一個態樣中，預防性治療包括向先前經歷所治療之疾病的至少一種症狀，且當前處於緩解中之哺乳動物投與醫藥組合物以預防疾病或病狀之症狀的復發，該醫藥組合物包含本文所述之化合物或其醫藥學上可接受之鹽。 在患者之病狀並未改良之某些實施例中，根據醫生之判斷，長期投與化合物，亦即持續較長時段，包括患者壽命之整個持續時間，以改善或以其他方式控制或限制患者之疾病或病狀之症狀。 在患者之狀況有所改良之某些實施例中，所投與之藥物的劑量暫時減少或暫時暫停一定時長(亦即「藥物假期」)。在特定實施例中，藥物假期之長度在2天與1年之間，包括僅例如2天、3天、4天、5天、6天、7天、10天、12天、15天、20天、28天或大於28天。藥物假期期間之劑量減少僅例如10%至100%，包括僅例如10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%及100%。 一旦患者之病狀發生改良，則在必要時投與維持劑量。隨後，在特定實施例中，根據症狀減少投藥之劑量或頻率或兩者，達至保持改良之疾病、病症或病狀之程度。然而，在某些實施例中，患者需要長期間歇治療以防任何症狀復發。 對應於此類量的所給藥劑之量視諸如以下因素而變化：特定化合物、疾病病狀及其嚴重程度、個體特性(例如體重、性別)或需要治療之主體，然而其係根據病例周圍之特定情況來確定，包括例如所投與之特定藥劑、投藥途徑、所治療之病狀及所治療之個體或主體。 然而，一般而言，用於成人治療之劑量通常在每天0.01 mg至5000 mg之範圍內。在一個態樣中，用於成人治療之劑量為每天約1 mg至約1000 mg。在一個實施例中，所需劑量宜以單次劑量或同時或以適當間隔投與之分次劑量(例如以每天兩次、三次、四次或大於四次之子劑量)呈現。 在一個實施例中，適於本文所述之化合物或其醫藥學上可接受之鹽的日劑量為每千克體重約0.01至約50 mg。在一些實施例中，基於關於個別治療方案之許多變數，劑型中活性物之日劑量或量低於或高於本文所指示之範圍。在各種實施例中，每日及單位劑量視許多變數而變化，該等變數包括(但不限於)所用化合物之活性、待治療之疾病或病狀、投藥模式、個別個體之需求、所治療之疾病或病狀之嚴重程度及醫師之判斷。 此類治療方案之毒性及治療功效係藉由標準醫藥程序在細胞培養物或實驗動物中來測定，包括(但不限於) LD50 及ED50 之測定。毒性與治療作用之間的劑量比為治療指數且其表示為LD50 與ED50 之間的比率。在某些實施例中，在調配用於哺乳動物，包括人類之治療有效日劑量範圍及/或治療有效單位劑量量中使用獲自細胞培養分析及動物研究之資料。在一些實施例中，本文所述化合物之日劑量量處於包括具有最小毒性之ED50 的循環濃度之範圍內。在某些實施例中，視所用劑型及所採用之投藥途徑而定，日劑量範圍及/或單位劑量量在此範圍內變化。 前述態樣中之任一者為將有效量之本文所述之化合物或其醫藥學上可接受之鹽：(a)全身性地投與哺乳動物；及/或(b)經口投與哺乳動物；及/或(c)靜脈內投與哺乳動物；及/或(d)藉由注射投與哺乳動物；及/或(e)表面投與哺乳動物；及/或(f)非全身性地或局部投與哺乳動物之其他實施例。 前述態樣中之任一者為包含單次投與有效量之化合物的其他實施例，其包括其中(i)向哺乳動物投與化合物一日一次或(ii)在一天內向哺乳動物投與化合物多次的其他實施例。 前述態樣中之任一者為包含多次投與有效量之化合物之其他實施例，其包括(i)連續或間歇地投與呈單次劑量之化合物；(ii)多次投藥之間的時間為每6小時；(iii)每8小時將化合物投與哺乳動物；(iv)每12小時將化合物投與哺乳動物；(v)每24小時投與化合物之其他實施例。在其他或替代實施例中，該方法包含藥物假期，其中將化合物之投與暫時暫停或將化合物之投與劑量暫時減少；在藥物假期結束時，恢復化合物之投與。在一個實施例中，藥物假期之長度在2天至1年間變化。 在某些情況下，宜投與至少一種本文所述之化合物或其醫藥學上可接受之鹽以及一或多種其他治療劑。 在一個實施例中，本文所述化合物中之一者的治療效應係藉由投與佐劑來增強(亦即佐劑本身具有最小治療效益，但與其他治療劑組合，會增強對患者之整體治療效益)。或者，在一些實施例中，患者所經歷之效益係藉由投與本文所述化合物中之一者與亦具有治療效益之另一藥劑(其亦包括治療方案)而增加。 在一個特定實施例中，本文所述之化合物或其醫藥學上可接受之鹽與第二治療劑共投與，其中本文所述之化合物或其醫藥學上可接受之鹽及第二治療劑調節所治療之疾病、病症或病狀的不同態樣，由此提供比單獨投與任一治療劑要更好之總體效益。 在任何情況下，不論所治療之疾病、病症或病況如何，患者所經歷之總體效益可為兩種治療劑相加，或患者可經歷協同效益。 在某些實施例中，當本文所揭示之化合物與一或多種諸如其他治療有效藥物、佐劑或其類似者之其他藥劑組合投與時，在調配醫藥組合物中及/或在治療方案中將採用不同治療有效劑量之本文所揭示之化合物。用於組合治療方案之藥物及其他藥劑之治療有效劑量視情況藉由與上文針對活性劑本身所述類似之方式測定。此外，本文所述之預防/治療方法涵蓋使用節拍式給藥，亦即提供較頻繁之較低劑量以使毒副作用降至最低。在一些實施例中，組合治療方案涵蓋在用本文所述之第二藥劑治療之前、期間或之後開始投與本文所述之化合物或其醫藥學上可接受之鹽，且持續至用第二藥劑治療期間或在用第二藥劑治療結束後之任何時間之治療方案。其亦包括其中在治療期期間同時或在不同時間及/或以減少或增加之時間間隔投與組合使用的本文所述之化合物或其醫藥學上可接受之鹽及第二藥劑的治療。組合治療進一步包括在各個時間開始及結束之週期性治療以協助患者之臨床管理。 應瞭解，治療、預防或改善尋求緩解之病狀之給藥方案會根據多種因素(例如個體所患之疾病、病症或病狀；個體之年齡、體重、性別、飲食及醫學病狀)進行調節。因此，在一些情況下，實際採用之給藥方案有所變化，且在一些實施例中，偏離本文所述之給藥方案。 對於本文所述之組合療法，共投與化合物之劑量視所用共同藥物之類型、所用之特定藥物、所治療之疾病或病狀等等而變化。在其他實施例中，當與一或多種其他治療劑共投與時，本文所提供之化合物與一或多種其他治療劑同時或連續投與。 在組合療法中，多種治療劑(其中一者為本文所述化合物中之一者)以任何次序或甚至同時投與。若同時投與，多種治療劑僅例如以單一統一形式或以多種形式(例如以單一丸劑或以兩種獨立丸劑)提供。 在疾病或病狀出現之前、期間或之後投與本文所述之化合物或其醫藥學上可接受之鹽以及組合療法，且投與含有化合物之組合物的時間選擇會有所變化。因此，在一個實施例中，將本文所述化合物用作防治性的，且連續投與傾向罹患病狀或疾病之個體以預防疾病或病狀出現。在另一個實施例中，在症狀發作期間或在症狀發作之後儘快向個體投與化合物及組合物。在特定實施例中，在偵測到或所懷疑之疾病或病狀發作之後在可行之情況下儘快投與本文所述化合物，且持續治療疾病所需之時長。在一些實施例中，治療所需之時長不同，且治療時長經調節以適合各個體之特定需求。舉例而言，在特定實施例中，投與本文所述化合物或含有該化合物之調配物持續至少2週、約1個月至約5年。 在一些實施例中，FXR促效劑與用於治療糖尿病或糖尿病相關病症或病狀之額外治療劑組合投與。 在一些情況下，額外治療劑包含斯他汀(statin)、胰島素敏化藥物、胰島素促泌素、α-葡糖苷酶抑制劑、GLP促效劑、DPP-4抑制劑(諸如西他列汀(sitagliptin)、維格列汀(vildagliptin)、沙格列汀(saxagliptin)、利格列汀(linagliptin)、阿拉格列汀(anaglptin)、替格列汀(teneligliptin)、阿格列汀(alogliptin)、吉格列汀(gemiglptin)或度格列汀(dutoglpitin))、兒茶酚胺(諸如腎上腺素、去甲腎上腺素或多巴胺)、過氧化體增殖物活化受體(PPAR)-γ促效劑(例如噻唑啶二酮(TZD) [諸如吡格列酮(pioglitazone)、羅格列酮(rosiglitazone)、利格列酮(rivoglitazone)或曲格列酮(troglitazone)]、阿格列紮(aleglitazar)、法格列紮(farglitazar)、莫格列紮(muraglitazar)或替格列紮(tesaglitazar))或其組合。在一些情況下，斯他汀為HMG-CoA還原酶抑制劑。在其他情況下，額外治療劑包括魚油、纖維酸酯、維生素(諸如菸酸、視黃酸(例如9順式視黃酸)、菸鹼醯胺核苷或其類似物)或其組合。在一些情況下，菸鹼醯胺核苷或其類似物會促進產生NAD+ ，該NAD+ 為多種酶促反應，包括p450之底物，該p450為FXR之靶向物(參見例如Yang等人,J. Med. Chem. 50:6458-61, 2007)。 在一些實施例中，FXR促效劑與額外治療劑組合投與以用於治療糖尿病或糖尿病相關病症或病狀，諸如斯他汀、胰島素敏化藥物、胰島素促泌素、α-葡糖苷酶抑制劑、GLP促效劑、DPP-4抑制劑(諸如西他列汀、維格列汀、沙格列汀、利格列汀、阿拉格列汀、替格列汀、阿格列汀、吉格列汀或度格列汀)、兒茶酚胺(諸如腎上腺素、去甲腎上腺素或多巴胺)、過氧化體增殖物活化受體(PPAR)-γ促效劑(例如噻唑啶二酮(TZD) [諸如吡格列酮、羅格列酮、利格列酮或曲格列酮]、阿格列紮、法格列紮、莫格列紮或替格列紮)或其組合。在一些實施例中，FXR促效劑與額外治療劑組合投與以用於治療糖尿病或糖尿病相關病症或病狀，該治療劑為諸如魚油、纖維酸酯、維生素(諸如菸酸、視黃酸(例如9順式視黃酸)、菸鹼醯胺核苷或其類似物)或其組合。 在一些實施例中，FXR促效劑與斯他汀，諸如HMG-CoA還原酶抑制劑、魚油、纖維酸酯、菸酸或其組合組合投與以用於治療血脂異常。 在其他實施例中，FXR促效劑與維生素，諸如視黃酸組合投與以用於治療糖尿病及糖尿病相關病症或病狀，諸如降低升高之體重及/或降低由食物攝入引起的升高之血糖。 在一些實施例中，法尼醇X受體促效劑與至少一種額外療法一起投與。在一些實施例中，至少一種額外療法為降葡萄糖劑。在一些實施例中，至少一種額外療法為抗肥胖劑。在一些實施例中，至少一種額外療法係選自以下之中：過氧化體增殖物活化受體(PPAR)促效劑(γ、雙重或泛)、二肽基肽酶(IV)抑制劑、類升糖素肽-1 (GLP-I)類似物、胰島素或胰島素類似物、胰島素促泌素、鈉葡萄糖共轉運體2 (SGLT2)抑制劑、格華止(glucophage)、人類澱粉素類似物、二胍、α-葡糖苷酶抑制劑、美格替耐(meglitinide)、噻唑啶二酮及磺醯脲。在一些實施例中，至少一種額外療法為二甲雙胍、西他列汀、沙格列汀、瑞格列奈(repaglinide)、那格列奈(nateglinide)、艾塞那肽(exenatide)、利拉魯肽(liraglutide)、賴脯胰島素、門冬胰島素、甘精胰島素、地特胰島素、魚精蛋白胰島素及類升糖素肽1或其任何組合。在一些實施例中，至少一種額外療法為降脂質劑。在某些實施例中，至少一種額外療法與法尼醇X受體促效劑同時投與。在某些實施例中，至少一種額外療法之投與頻率要低於法尼醇X受體促效劑。在某些實施例中，至少一種額外療法之投與頻率要高於法尼醇X受體促效劑。在某些實施例中，在投與法尼醇X受體促效劑之前投與至少一種額外療法。在某些實施例中，在投與法尼醇X受體促效劑之後投與至少一種額外療法。 在一些實施例中，本文所述之化合物或其醫藥學上可接受之鹽與化學療法、消炎劑、輻射療法、單株抗體或其組合組合投與。 在一些實施例中，FXR促效劑與用於治療酒精性或非酒精性肝臟疾病之額外治療劑組合投與。在一些實施例中，額外治療劑包括抗氧化劑、皮質類固醇、抗腫瘤壞死因子(anti-tumor necrosis factor；TNF)或其組合。 在一些實施例中，FXR促效劑與用於治療酒精性或非酒精性肝臟疾病之額外治療劑組合投與，諸如抗氧化劑、皮質類固醇、抗腫瘤壞死因子(TNF)或其組合。在一些實施例中，FXR促效劑與抗氧化劑、維生素前驅體、皮質類固醇、抗腫瘤壞死因子(TNF)或其組合組合投與以用於治療酒精性或非酒精性肝臟疾病。 在一些實施例中，FXR促效劑與用於治療炎症相關腸道病狀之額外治療劑組合投與。在一些情況下，額外治療劑包含抗生素(諸如甲硝噠唑、萬古黴素(vancomycin)及/或非達黴素(fidaxomicin))、皮質類固醇或其他消炎或免疫調節療法。 在一些情況下，FXR促效劑與額外治療劑，諸如抗生素、皮質類固醇或其他消炎或免疫調節療法組合投與以用於治療之炎症相關腸道病狀。在一些情況下，FXR促效劑與甲硝噠唑、萬古黴素、非達黴素、皮質類固醇或其組合組合投與以用於治療炎症相關腸道病狀。 如上文所論述，炎症有時與偽膜性結腸炎相關聯。在一些情況下，偽膜性結腸炎與細菌過度生長(諸如艱難梭菌(C . dificile )過度生長)相關聯。在一些實施例中，FXR促效劑與抗生素，諸如甲硝噠唑、萬古黴素、非達黴素或其組合組合投與以用於治療與細菌過度生長相關聯之炎症(例如偽膜性結腸炎)。 在一些實施例中，FXR促效劑與用於治療細胞增殖性病症之額外治療劑組合投與。在一些實施例中，額外治療劑包括化學治療劑、生物治療劑(例如抗體，例如貝伐單抗(bevacizumab)、西妥昔單抗(cetuximab)或帕尼單抗(panitumumab))、放射線治療劑(例如FOLFOX、FOLFIRI、CapeOX、5-FU、甲醯四氫葉酸、瑞戈非尼(regorafenib)、伊立替康(irinotecan)或奧沙利鉑(oxaliplatin))或其組合。 在一些實施例中，FXR促效劑與用於治療原發性膽汁性肝硬化症之額外治療劑組合投與。在一些實施例中，額外治療劑包括熊脫氧膽酸(UDCA)。 在一些實施例中，FXR促效劑與額外治療劑，諸如化學治療劑、生物治療劑、放射線治療劑或其組合組合投與以用於治療細胞增殖性病症。在一些情況下，FXR促效劑與抗體(例如貝伐單抗、西妥昔單抗或帕尼單抗)、化學治療劑、FOLFOX、FOLFIRI、CapeOX、5-FU、甲醯四氫葉酸、瑞戈非尼、伊立替康、奧沙利鉑或其組合組合投與以用於治療細胞增殖性病症。實例 提供以下實例僅為達成說明之目的且並不限制本文所提供之申請專利範圍之範疇。 如上文及本發明說明書通篇中所用，除非另有指示，否則以下縮寫應理解為具有以下含義： ACN或MeCN 乙腈 AcOH 乙酸 Ac 乙醯基 BINAP 2,2'-雙(二苯膦基)-1,1'-聯萘 Bn 苯甲基 BOC或Boc 胺基甲酸第三丁酯 t-Bu 第三丁基 Cy 環己基 DBA或dba 二亞苄基丙酮 DCE 二氯乙烷(ClCH2 CH2 Cl) DCM 二氯甲烷(CH2 Cl2 ) DIPEA或DIEA 二異丙基乙胺 DMAP 4-(N,N -二甲胺基)吡啶 DME 1,2-二甲氧乙烷 DMFN,N -二甲基甲醯胺 DMAN,N -二甲基乙醯胺 DMSO 二甲亞碸 Dppf或dppf 1,1'-雙(二苯膦基)二茂鐵 EEDQ 2-乙氧基-1-乙氧基羰基-1,2-二氫喹啉 eq 當量 Et 乙基 Et2 O 乙醚 EtOH 乙醇 EtOAc 乙酸乙酯 HATU 1-[雙(二甲胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡錠3-氧化物六氟磷酸鹽 HMPA 六甲基磷醯胺 HPLC 高效液相層析法 KHMDS 雙(三甲基矽烷基)胺基鉀 NaHMDS 雙(三甲基矽烷基)胺基鈉 LiHMDS 雙(三甲基矽烷基)胺基鋰 LAH 鋁氫化鋰 LCMS 液相層析質譜分析 Me 甲基 MeOH 甲醇 MS 質譜分析 Ms 甲磺醯基 NBSN -溴代丁二醯亞胺 NMMN -甲基-嗎啉 NMPN -甲基-吡咯啶-2-酮 NMR 核磁共振 PCC 氯鉻酸吡錠 Ph 苯基 PPTS 對甲苯磺酸吡錠 iPr/i-Pr 異丙基 TBS 第三丁基二甲基矽烷基 RP-HPLC 逆相-高壓液相層析法 TFA 三氟乙酸 TEA 三乙胺 THF 四氫呋喃 TLC 薄層層析法中間物 1 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己烷甲醛
Figure 02_image235
步驟 1 ： 8 -( 4 - 甲氧基 - 3 - 甲基苯基 )- 1 , 4 - 二氧雜螺 [ 4 . 5 ] 癸 - 7 - 烯 用3次真空/N2 循環使1,4-二氧雜-螺[4,5]癸-7-烯-8-
Figure 107108918-A0304-12-0030-1
酸四甲基乙二醇酯(25.0 g，93.9 mmol)、4-碘-2-甲基苯甲醚(28.0 g，113 mmol)、1,1'-雙(二苯膦基)二茂鐵二氯化鈀(II) (1.38 g，1.89 mmol)、二噁烷(470 mL)及1 M Na2 CO3 (282 mL，282 mmol)之混合物脫氣，在50℃下攪拌2.5小時，且隨後使其冷卻至室溫。用EtOAc (500 mL)稀釋混合物且用飽和NaHCO3 (2 × 500 mL)洗滌。用EtOAc (200 mL)反萃取水層。乾燥(Na2 SO4 )經合併之EtOAc萃取物，過濾，濃縮且藉由矽膠層析法(0%至5% EtOAc/己烷)純化，得到8-(4-甲氧基-3-甲基苯基)-1,4-二氧雜螺[4.5]癸-7-烯(19.9 g，81%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 7.21-7.16 (m, 2H), 6.85 (d, 1H), 5.89-5.84 (m, 1H), 3.90 (s, 4H), 3.76 (s, 3H), 2.52-2.47 (m, 2H), 2.32 (br s, 2H), 2.13 (s, 3H), 1.77 (t, 2H)；LCMS: 261.1 [M+H]+ 。步驟 2 ： 8 -( 4 - 甲氧基 - 3 - 甲基苯基 )- 1 , 4 - 二氧雜螺 [ 4 . 5 ] 癸烷 在室溫下在N2 下將鈀/碳(10 wt%，8.08 g，7.59 mmol)添加至8-(4-甲氧基-3-甲基苯基)-1,4-二氧雜螺[4.5]癸-7-烯(19.8 g，76.1 mmol)於EtOAc (300 mL)中之溶液中。N2 入口用H2 氣球替代。攪拌反應持續4.5小時，經由矽藻土及EtOAc過濾，且隨後濃縮得到呈白色固體狀之8-(4-甲氧基-3-甲基苯基)-1,4-二氧雜螺[4.5]癸烷(18.2 g；含有13%酮)。1 H NMR (400 MHz, DMSO-d 6 ): δ 7.00-6.95 (m, 2H), 6.81 (d, 1H), 3.91-3.84 (m, 4H), 3.73 (s, 3H), 2.49-2.42 (m, 1H), 2.11 (s, 3H), 1.76-1.68 (m, 4H), 1.67-1.55 (m, 4H)；LCMS: 263.1 [M+H]+ 。步驟 3 ： 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己酮 在室溫下在N2 下將甲酸(96%，14 mL，356 mmol)，且隨後將水(2.20 mL，122 mmol)添加至8-(4-甲氧基-3-甲基苯基)-1,4-二氧雜螺[4.5]癸烷(18.2 g)於甲苯(60 mL)中之溶液中。在120℃下加熱反應持續4小時，使其冷卻至室溫，且隨後倒入200 mL H2 O及200 mL甲苯中。用200 mL H2 O，且隨後用200 mL飽和NaHCO3 洗滌甲苯層。用100 mL甲苯反萃取水層。乾燥(Na2 SO4 )經合併之甲苯萃取物，過濾且濃縮，得到呈白色固體狀之4-(4-甲氧基-3-甲基苯基)環己酮(15.5 g，歷經2個步驟呈88%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 7.08-7.03 (m, 2H), 6.84 (d, 1H), 3.74 (s, 3H), 3.00-2.91 (m, 1H), 2.61-2.51 (m, 2H), 2.28-2.20 (m, 2H), 2.12 (s, 3H), 2.06-1.98 (m, 2H), 1.88-1.76 (m, 2H)；LCMS: 219.0 [M+H]+ 。步驟 4 ： 1 - 甲氧基 - 4 -( 4 -( 甲氧基亞甲基 ) 環己基 )- 2 - 甲基苯 在N2 下在冰/鹽水浴中將(甲氧基甲基)三苯基氯化鏻(35.74 g，104.3 mmol)及THF (260 mL)之混合物冷卻至-2.2℃。歷經12分鐘經由加料漏斗逐滴添加雙(三甲基矽烷基)胺基鈉溶液(2 M於THF中，50 mL，100 mmol) (內部溫度≤ 0.6℃)，且用THF (5 mL)沖洗。攪拌反應30分鐘，且隨後歷經5分鐘逐份添加4-(4-甲氧基-3-甲基苯基)環己酮(14.5 g，66.6 mmol) (放熱至7.3℃)。用THF (20 mL)將殘餘環己酮沖洗至反應中。在0℃下攪拌反應25分鐘，且隨後倒入400 mL H2 O及400 mL甲苯中。用400 mL H2 O洗滌甲苯層，乾燥(Na2 SO4 )，過濾，濃縮且藉由矽膠層析法(0%至5% EtOAc/己烷)純化，得到呈淡金色油狀之1-甲氧基-4-(4-(甲氧基亞甲基)環己基)-2-甲基苯(15.6 g，95%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 6.99-6.94 (m, 2H), 6.80 (d, 1H), 5.87 (s, 1H), 3.73 (s, 3H), 3.48 (s, 3H), 2.78-2.71 (m, 1H), 2.56-2.44 (m, 1H), 2.10 (s, 3H), 2.17-2.09 (m, 1H), 2.01-1.91 (m, 1H), 1.83-1.73 (m, 2H), 1.72-1.63 (m, 1H), 1.38-1.23 (m, 2H)；LCMS: 247.1 [M+H]+ 。步驟 5 ： 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己烷甲醛 在N2 下將甲酸(96%，12.5 mL，331 mmol)，且隨後將水(2.5 mL，139 mmol)添加至1-甲氧基-4-(4-(甲氧基亞甲基)環己基)-2-甲基苯(16.05 g，65.15 mmol)於甲苯(130 mL)中之溶液中。在120℃下加熱反應2小時，使其冷卻至室溫，且隨後倒入350 mL EtOAc及350 mL H2 O中。用350 mL H2 O洗滌有機層，乾燥(Na2 SO4 )，過濾且濃縮，得到呈立體異構體之1:1混合物形式之4-(4-甲氧基-3-甲基苯基)環己烷甲醛(15.05 g)。步驟 6 ： 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己烷甲醛 在室溫下將氫氧化鈉水溶液(3.2 M，31 mL，99 mmol)添加至來自步驟5之粗混合物(14.68 g，63.19 mmol)、甲苯(60 mL)及乙醇(250 mL)中。攪拌反應5.5小時(藉由NMR監測平衡)，且隨後倒入350 mL H2 O及350 mL EtOAc中。用350 mL H2 O洗滌有機層，且用150 mL EtOAc反萃取水層。乾燥(Na2 SO4 )經合併之萃取物，過濾，濃縮且藉由矽膠層析法(0%至5% EtOAc/己烷)純化，得到呈白色固體狀之反-4-(4-甲氧基-3-甲基苯基)環己烷甲醛(10.17 g，69%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 9.60 (s, 1H), 7.01-6.97 (m, 2H), 6.82 (d, 1H), 3.74 (s, 3H), 2.41-2.27 (m, 2H), 2.12 (s, 3H), 2.03-1.96 (m, 2H), 1.87-1.80 (m, 2H), 1.51-1.39 (m, 2H), 1.35-1.23 (m, 2H)；LCMS: 233.0 [M+H]+ 。 遵循針對中間物 1 所述之程序由合適芳基鹵化物(SM或中間物)合成以下中間物。
Figure AA10
 替代條件：步驟1：1 EtOH、DME，100℃，5小時；2 EtOH、二噁烷，100℃，隔夜；3 Cs2 CO3 、二噁烷，100℃，6小時；4 Pd(PPh3 )4 ，100℃，5小時；5 Pd(PPh3 )4 、CH3 CN/H2 O，回流，隔夜；步驟2：6 MeOH；7 HCl、EtOAc；步驟3：8 PPTS、丙酮、H2 O，60℃ 10小時；9 3 M HCl、THF，60℃，3小時至隔夜；步驟4：10 LiHMDS (1 M THF)，0℃或室溫0.5至2小時；步驟5：11 3 M HCl、THF，室溫或60℃，1至6小時；步驟6：12 NaOMe、MeOH，室溫，4小時至至隔夜。中間物 2 反 - 4 -( 3 - 氯 - 4 - 甲氧基苯基 ) 環己烷甲醛
Figure 02_image259
步驟 1 ： 8 -( 3 - 氯 - 4 - 甲氧基苯基 )- 1 , 4 - 二氧雜螺 [ 4 . 5 ] 癸 - 8 - 醇 向3頸圓底燒瓶中添加4-溴-2-氯-1-甲氧基-苯(45.00 g，203.18 mmol)及THF(450 mL)，在-78℃下添加正丁基鋰(2.5 M之己烷溶液，90.21 mL，1.11 eq)。在-78℃下攪拌混合物2小時。將1,4-二氧雜螺[4.5]癸-8-酮(34.91 g，223.50 mmol)於THF (90 mL)中之溶液逐滴添加至反應混合物中。在-78℃下攪拌所得混合物3小時。用NH4 Cl水溶液(100 mL)淬滅反應且用EtOAc (500 mL)萃取。乾燥(Na2 SO4 )有機層，過濾且濃縮。用己烷(350 mL)洗滌殘餘物，過濾且高真空乾燥。用己烷(15 mL)濕磨固體，過濾且高真空乾燥，得到呈白色固體狀之8-(3-氯-4-甲氧基-苯基)-1,4-二氧雜螺[4.5]癸-8-醇(37 g，61%)。1 H NMR (400 MHz, CDCl3 ): δ 7.31 (d, 1H), 7.29 (dd, 1H), 7.10 (d, 1H), 3.90-3.92 (m, 4H), 3.89 (s, 3H), 1.99-2.02 (m, 4H), 1.70-1.73 (m, 4H)；LCMS: 281.2 [M-OH]+ 。步驟 2 ： 8 -( 3 - 氯 - 4 - 甲氧基苯基 )- 1 , 4 - 二氧雜螺 [ 4 . 5 ] 癸烷 在0℃下將三乙基矽烷(19.26 g，165.6 mmol)、TFA (25.18 g，220.8 mmol)及DCM (100 mL)之溶液逐滴添加至8-(3-氯-4-甲氧基苯基)-1,4-二氧雜螺[4.5]癸-8-醇(31.0 g，110.4 mmol)及DCM (200 mL)之溶液中。在室溫下攪拌反應混合物隔夜且隨後冷卻至0℃。用NaHCO3 水溶液將pH調整至約8且用DCM (2 × 100 mL)萃取混合物。乾燥(Na2 SO4 )有機層，過濾，且濃縮至乾燥，得到呈黃色油狀之8-(3-氯-4-甲氧基苯基)-1,4-二氧雜螺[4.5]癸烷(38 g，粗物質)，其含有少量8-(3-氯-4-甲氧基苯基)-1,4-二氧雜螺[4.5]癸-7-烯。LCMS: 283.1 [M+H]+ 。步驟 3 ： 4 -( 3 - 氯 - 4 - 甲氧基苯基 ) 環己酮 用3次真空/N2 循環使8-(3-氯-4-甲氧基苯基)-1,4-二氧雜螺[4.5]癸烷(38.0 g，134 mmol)、甲酸(32.3 g，672 mmol)、H2 O (4.84 g，269 mmol)及甲苯(400 mL)之混合物脫氣，在130℃下攪拌隔夜，且隨後用H2 O (200 mL)及飽和NaHCO3 (200 mL)洗滌。用甲苯(300 mL)萃取經合併之水層。乾燥(Na2 SO4 )有機層，過濾且濃縮至乾燥。濕磨(PE:EtOAc = 10:1，80 mL)殘餘物，得到呈淡黃色固體狀之4-(3-氯-4-甲氧基苯基)環己酮(20 g，54%)，其含有少量3'-氯-4'-甲氧基-5,6-二氫-[1,1'-聯苯]-4(3H )-酮。將此固體(5.00 g，21.12 mmol)添加至Pd/C (10 wt.%，820 mg，0.77 mmol)、HCl (12 M，1.00 mL)及EtOAc (100 mL)之混合物中。用3次真空/N2 循環使所得混合物脫氣，在H2 (15 psi)下在室溫下攪拌30分鐘，過濾且隨後用EtOAc (50 mL)稀釋。用水(100 mL)洗滌且用飽和NaHCO3 (100 mL)洗滌混合物。用EtOAc (100 mL)萃取水相。乾燥(Na2 SO4 )經合併之有機層，過濾，且濃縮至乾燥，得到呈黃色固體狀之4-(3-氯-4-甲氧基苯基)環己酮(4.60 g，84%)。1 H NMR (400 MHz, CDCl3 ): δ 7.24 (d, 1H), 7.09 (dd, 1H), 6.88 (d, 1H), 3.90 (s, 3H), 2.88-3.05 (m, 1H), 2.44-2.54 (m, 4H), 2.12-2.25 (m, 2H), 1.79-1.96 (m, 2H)；LCMS: 239.1 [M+H]+ 。步驟 4 ： 2 - 氯 - 1 - 甲氧基 - 4 -( 4 -( 甲氧基亞甲基 ) 環己基 ) 苯 在0℃下將雙(三甲基矽烷基)胺基鋰(1 M，36 mL)逐滴添加至甲氧基甲基(三苯基)氯化鏻(12.24 g，35.71 mmol)及THF (80 mL)之混合物中。在0℃下攪拌混合物2小時。在0℃下逐滴添加4-(3-氯-4-甲氧基-苯基)環己酮(5.50 g，23.04 mmol)於THF (20 mL)中之溶液。在0℃下攪拌所得混合物3小時。藉由H2 O (100 mL)淬滅反應混合物且用EtOAc (3 × 100 mL)萃取。用鹽水(200 mL)洗滌經合併之有機層，乾燥(Na2 SO4 )，過濾，濃縮，且藉由矽膠層析法(石油醚/乙酸乙酯= 20:1)純化，得到呈黃色油狀之2-氯-1-甲氧基-4-(4-(甲氧基亞甲基)環己基)苯(5 g，77%)。LCMS: 267.1 [M+H]+ 。步驟 5 ： 4 -( 3 - 氯 - 4 - 甲氧基苯基 ) 環己烷甲醛 用3次真空/N2 循環使2-氯-1-甲氧基-4-(4-(甲氧基亞甲基)環己基)苯(5.00 g，18.74 mmol)、甲酸(4.50 g，93.7 mmol)、H2 O (675.5 mg，37.48 mmol)及甲苯(100 mL)之混合物脫氣，在130℃下攪拌隔夜，使其冷卻至室溫，且隨後用H2 O (200 mL)洗滌，且用飽和NaHCO3 (200 mL)洗滌。用甲苯(300 mL)萃取經合併之水層。乾燥(Na2 SO4 )有機層，過濾，且濃縮至乾燥，得到呈黃色油狀之順式/反式異構體之混合物，4-(3-氯-4-甲氧基-苯基)環己烷甲醛(5.60 g，粗物質)。步驟 6 ： 反 - 4 -( 3 - 氯 - 4 - 甲氧基苯基 ) 環己烷甲醛 將NaOH (992.6 mg，24.82 mmol)於H2 O (12 mL)中之溶液添加至來自步驟5之粗混合物(5.60 g，15.51 mmol)、EtOH (90 mL)及甲苯(15 mL)中。在室溫下攪拌混合物隔夜，用H2 O (100 mL)淬滅，且隨後用EtOAc (3 × 100 mL)萃取。藉由鹽水(200 mL)洗滌經合併之有機層，乾燥(Na2 SO4 )，過濾且濃縮至乾燥，得到殘餘物。藉由矽膠層析法(石油醚/乙酸乙酯= 20:1)純化殘餘物，且隨後用MTBE (20 mL)濕磨，得到呈白色固體狀之反-4-(3-氯-4-甲氧基苯基)環己烷甲醛(1.96 g，49%)。1 H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 7.27 (d, 1H), 7.16 (dd, 1H), 7.05 (d, 1H), 3.81 (s, 3H), 2.43 (m, 1H), 2.27-2.37 (m, 1H), 1.95-2.05 (m, 2H), 1.84 (m, 2H), 1.45 (m, 2H), 1.21-1.35 (m, 2H)；LCMS: 253.1 [M+H]+ 。 遵循針對中間物 2 所述之程序由4-溴-1-甲氧基-2-甲基苯合成以下中間物。
Figure AA11
 替代條件：步驟1：-60℃；步驟2：0℃，1小時；步驟3a：THF代替PhMe，80℃，18小時；步驟3b：無HCl，30 psi H2 ，18小時；步驟4：15小時；步驟5：3 N HCl、THF，60℃，1小時；步驟6：THF代替PhMe。中間物 3 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 雙環 [ 2 . 2 . 2 ] 辛烷 - 1 - 甲醛
Figure 02_image263
步驟 1 ： 4 - 羥基 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己烷甲酸乙酯 在-78℃下將正丁基鋰(2.5 M之己烷溶液，60 mL，150.0 mmol)逐滴添加至4-溴-1-甲氧基-2-甲基苯(27.78 g，138.2 mmol)於THF (300 mL)中之溶液中。在-78℃下攪拌混合物1小時，且隨後在-78℃下逐滴添加至4-側氧基環己烷甲酸乙酯(22.34 g，131.3 mmol)於THF (300 mL)中之溶液中。在-78℃下攪拌混合物2小時，添加至飽和NH4 Cl (600 mL)中，且隨後用EtOAc (2 × 600 mL)萃取。用水(400 mL)洗滌經合併之有機萃取物，用鹽水(400 mL)洗滌，乾燥(Na2 SO4 )，過濾，濃縮，且藉由矽膠層析法(石油醚/EtOAc = 10/1)純化，得到呈黃色油狀之4-羥基-4-(4-甲氧基-3-甲基苯基)環己烷甲酸乙酯(18.9 g，45%)。1 H NMR (400 MHz, DMSO): δ 7.11-7.26 (m, 2H), 6.75-6.84 (m, 1H), 4.59-4.64 (m, 1H), 3.98-4.11 (m, 2H), 3.72 (s, 3H), 2.25-2.39 (m, 1H), 2.07-2.13 (s, 3H), 1.77-1.93 (m, 3H), 1.42-1.75 (m, 5H), 1.11-1.23 (m, 3H)；LCMS: 275.2 [M-OH]+ 。步驟 2 ： 4 - 烯丙基 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己烷甲酸乙酯 在-78℃下將三氟化硼合二乙醚(24.85 g，84.03 mmol)添加至4-羥基-4-(4-甲氧基-3-甲基苯基)環己烷甲酸乙酯(18.90 g，64.64 mmol)及烯丙基三甲基矽烷(11.82 g，103.42 mmol)於DCM (400 mL)中之溶液中。在 -78℃下攪拌混合物1小時，在室溫下攪拌隔夜，且隨後添加至鹽水(200 mL)及DCM (200 mL)中。分離有機層，用飽和NaHCO3 (2 × 200 mL)洗滌，用鹽水(200 mL)洗滌，乾燥(Na2 SO4 )，過濾，濃縮，且藉由矽膠層析法(石油醚/EtOAc = 20/1)純化，得到呈黃色油狀之4-烯丙基-4-(4-甲氧基-3-甲基苯基)環己烷甲酸乙酯(15 g，71%)。1 H NMR (400 MHz, CDCl3 ): δ 7.00-7.10 (m, 2H), 6.76 (d, 1H), 5.26-5.50 (m, 1H), 4.81-4.98 (m, 2H), 4.15 (q, 0.5H), 4.03 (q, 1.5H), 3.81 (s, 3H), 2.26-2.42 (m, 3H), 2.21 (s, 3H), 2.15 (d, 1.5H), 1.98 (d, 0.5H), 1.75-1.88 (m, 2.5H), 1.60-1.72 (m, 0.5H), 1.33-1.55 (m, 3H), 1.27 (t, 0.8H), 1.18 (t, 2.2H)；LCMS: 339.3 [M+Na]+ 。步驟 3 ： 4 -( 2 , 3 - 二羥丙基 )- 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己烷甲酸乙酯 在0℃下將四氧化鋨(0.1 M於第三丁醇中，7.6 mL，0.76 mmol)添加至4-烯丙基-4-(4-甲氧基-3-甲基苯基)環己烷甲酸乙酯(4.81 g，15.2 mmol)、4-甲基嗎啉N -氧化物(2.67 g，22.8 mmol)、CH3 CN (100 mL)及H2 O (25 mL)之溶液中。在室溫下攪拌混合物隔夜。將飽和Na2 SO3 (50 mL)添加至混合物中。在室溫下攪拌混合物30分鐘，濃縮，溶解於水(80 mL)中且用EtOAc (2 × 100 mL)萃取。乾燥(Na2 SO4 )有機層，過濾，濃縮，且藉由矽膠層析法(石油醚/EtOAc = 1/1)純化，得到呈黃色油狀之4-(2,3-二羥丙基)-4-(4-甲氧基-3-甲基苯基)環己烷甲酸乙酯(5.23 g，94%)。1 H NMR (400 MHz, CDCl3 ): δ 7.05-7.16 (m, 2H), 6.78 (d, 1H), 4.06-4.17 (m, 0.5H), 3.95-4.05 (m, 1.5H), 3.80 (s, 3H), 3.48-3.66 (m, 1H), 3.18-3.32 (m, 2H), 2.40-2.53 (m, 2H), 2.27-2.37 (m, 1H), 2.19 (s, 3H), 1.80 (t, 3H), 1.32-1.68 (m, 7H), 1.24-1.25 (m, 0.8H), 1.17 (t, 2.2H)；LCMS: 373.3 [M+Na]+ 。步驟 4 ： 4 -( 4 - 甲氧基 - 3 - 甲基苯基 )- 4 -( 2 - 側氧基乙基 ) 環己烷甲酸乙酯 在0℃下將高碘酸鈉(3.83 g，17.90 mmol)添加至4-(2,3-二羥丙基)-4-(4-甲氧基-3-甲基苯基)環己烷甲酸乙酯(5.23 g，14.9 mmol)、THF (70 mL)及H2 O (35 mL)之溶液中。在室溫下攪拌混合物隔夜，且隨後添加至水(50 mL)及EtOAc (2 × 100 mL)中。分離有機層，用水(80 mL)洗滌，用鹽水(80 mL)洗滌，乾燥(Na2 SO4 )，過濾，濃縮且藉由矽膠層析法(石油醚/EtOAc = 5/1)純化，得到呈黃色油狀之4-(4-甲氧基-3-甲基苯基)-4-(2-側氧基乙基)環己烷甲酸乙酯(3.95 g，82%)。1 H NMR (400 MHz, CDCl3 ): δ 9.28-9.42 (m, 1H), 7.07-7.19 (m, 2H), 6.79 (d, 1H), 4.15 (q, 0.5H), 4.04 (q, 1.5H), 3.82 (s, 3H), 2.41-2.52 (m, 3H), 2.33 (s, 1H), 2.21 (s, 3H), 1.75-1.92 (m, 3H), 1.46-1.63 (m, 4H), 1.23-1.31 (t, 0.5H), 1.19 (t, 2.5H)；LCMS: 341.3 [M+Na]+ 。步驟 5 ： 4 -( 2 - 羥乙基 )- 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己烷甲酸乙酯 在0℃下將硼氫化鈉(704 mg，18.6 mmol)添加至4-(4-甲氧基-3-甲基苯基)-4-(2-側氧基乙基)環己烷甲酸乙酯(3.95 g，12.41 mmol)於THF (100 mL)中之溶液中。在0℃下攪拌混合物1小時，在室溫下攪拌隔夜，且隨後用水(100 mL)稀釋。在減壓下移除有機溶劑，且用DCM (2 × 300 mL)萃取水層。乾燥(Na2 SO4 )有機萃取物，過濾，濃縮，且藉由矽膠層析法(石油醚:EtOAc = 3:1)純化，得到呈黃色油狀之4-(2-羥乙基)-4-(4-甲氧基-3-甲基苯基)環己烷甲酸乙酯(3.11 g，67%)。1 H NMR (400 MHz, CDCl3 ): δ 6.96-7.04 (m, 2H), 6.71 (d, 1H), 4.03-4.12 (q, 0.4H), 3.97 (q, , 1.6H), 3.74 (s, 3H), 3.28-3.38 (m, 2H), 2.19-2.39 (m, 3H), 2.14 (s, 3H), 1.71-1.80 (m, 2H), 1.60-1.70 (m, 2H), 1.28-1.50 (m, 4H), 1.17-1.24 (t, 1H), 1.12 (t, 2H), (未偵測到OH質子)；LCMS: 343.2 [M+Na]+ 。步驟 6 ： 4 -( 2 - 溴乙基 )- 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己烷甲酸乙酯 在0℃下將三苯基膦(4.60 g，17.54 mmol)之DCM (20 mL)溶液逐滴添加至4-(2-羥乙基)-4-(4-甲氧基-3-甲基苯基)環己烷甲酸乙酯(2.81 g，8.77 mmol)、CBr4 (4.36 g，13.16 mmol)及DCM (40 mL)之溶液中。在0℃下攪拌混合物1小時，在室溫下攪拌隔夜，濃縮，且隨後藉由矽膠層析法(石油醚/EtOAc = 20/1)純化，得到呈黃色油狀之4-(2-溴乙基)-4-(4-甲氧基-3-甲基苯基)環己烷甲酸乙酯(2.62 g，77%)。1 H NMR (400 MHz, CDCl3 ): δ 6.96-7.08 (m, 2H), 6.77 (d, 1H), 4.15 (q, 0.3H), 4.03 (q, 1.7H), 3.81 (s, 3H), 2.91-3.06 (m, 2H), 2.24-2.41 (m, 3H), 2.15-2.24 (s, 3H), 1.95-2.06 (m, 2H), 1.77-1.87 (m, 2H), 1.34-1.53 (m, 4H), 1.27 (t, 1H), 1.18 (t, 2H)；LCMS: 405.1 [M+Na]+ 。步驟 7 ： 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 雙環 [ 2 . 2 . 2 ] 辛烷 - 1 - 甲酸乙酯 在-78℃下將二異丙胺基鋰(2M於THF中，4.8 mL，9.60 mmol)逐滴添加至4-(2-溴乙基)-4-(4-甲氧基-3-甲基苯基)環己烷甲酸乙酯(1.81 g，4.72 mmol)、HMPA (4.23 g，23.61 mmol)及THF (90 mL)之溶液中。在 -78℃下攪拌混合物3小時，添加至飽和NH4 Cl (90 mL)中，且隨後用EtOAc (2 × 150 mL)萃取。用水(100 mL)洗滌經合併之有機層，用鹽水(100 mL)洗滌，乾燥(Na2 SO4 )，過濾，濃縮，且藉由矽膠層析法(石油醚/EtOAc = 30/1)純化，得到呈黃色固體狀之4-(4-甲氧基-3-甲基苯基)雙環[2.2.2]辛烷-1-甲酸乙酯(1.17 g，82%)。1 H NMR (400 MHz, CDCl3 ): δ 6.98-7.05 (m, 2H), 6.69 (d, 1H), 4.05 (q, 2H), 3.73 (s, 3H), 2.14 (s, 3H), 1.70-1.87 (m, 12H), 1.18 (t, 3H)；LCMS: 303.3 [M+H]+ 。步驟 8 ： ( 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 雙環 [ 2 . 2 . 2 ] 辛 - 1 - 基 ) 甲醇 在-78℃下將二異丁基氫化鋁(1 M於甲苯中，14 mL，14.0 mmol)添加至4-(4-甲氧基-3-甲基苯基)雙環[2.2.2]辛烷-1-甲酸乙酯(1.64 g，5.42 mmol)於DCM (100 mL)中之溶液中。在-78℃下攪拌混合物1小時，在室溫下攪拌2小時，且隨後添加至冰水(80 mL)中。用1 N HCl將混合物調整至(pH = 6)且加以過濾。分離有機層，且用DCM (2 × 200 mL)萃取水層。用水(100 mL)洗滌經合併之有機層，用鹽水(100 mL)洗滌，乾燥(Na2 SO4 )，過濾且濃縮。藉由矽膠層析法(石油醚/EtOAc = 10/1)純化殘餘物，得到呈黃色固體狀之(4-(4-甲氧基-3-甲基苯基)雙環[2.2.2]辛-1-基)甲醇(1.22 g，82%)。1 H NMR (400 MHz, CDCl3 ): δ 6.99-7.07 (m, 2H), 6.64-6.72 (m, 1H), 3.73 (s, 3H), 3.25 (s, 2H), 2.14 (s, 3H), 1.69-1.81 (m, 6H), 1.40-1.50 (m, 6H)；LCMS: 261.2 [M+H]+ 。步驟 9 ： 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 雙環 [ 2 . 2 . 2 ] 辛烷 - 1 - 甲醛 將氯鉻酸吡錠(1.03 g，4.78 mmol)添加至(4-(4-甲氧基-3-甲基苯基)雙環[2.2.2]辛-1-基)甲醇(621.1 mg，2.39 mmol)、SiO2 (1.93 g，32.19 mmol)及DCM (120 mL)之混合物中。在室溫下攪拌混合物2小時，經由中性氧化鋁塞過濾且濃縮，得到呈白色固體狀之4-(4-甲氧基-3-甲基苯基)雙環[2.2.2]辛烷-1-甲醛(601.3 mg，93%)。1 H NMR (400 MHz, CDCl3 ): δ 9.48-9.56 (s, 1H), 7.06-7.11 (m, 2H), 6.72-6.78 (m, 1H), 3.81 (s, 3H), 2.22 (s, 3H), 1.83-1.91 (m, 6H), 1.71-1.80 (m, 6H)；LCMS: 259.3 [M+H]+ 。 遵循針對中間物 3 所述之程序由5-溴-N ,N -二甲基吡啶-2-胺合成以下中間物。
Figure AA12
 替代條件：步驟2：0℃，隔夜；步驟3：K2 OsO4 ·2H2 O；步驟7：-78℃，1小時隨後室溫，隔夜；步驟9：乙二醯氯、DMSO、Et3 N，-78℃。中間物 4 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 ) 苯胺
Figure 02_image267
用真空/N2 循環(3×)使3-碘苯胺(63.36 g，289.9 mmol)、Pd(dppf)Cl2 (7.05 g，9.63 mmol)、K2 CO3 (2.2 M，265 mL，583.0 mmol)及二噁烷(340 mL)之混合物脫氣。添加1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)-1H-吡唑(約90%，50.09 g，192.6 mmol)，且在經預加熱之油浴(90℃)中加熱混合物持續20分鐘(20分鐘下之內部溫度為72℃)。使反應冷卻至室溫，用EtOAc (800 mL)及H2 O (800 mL)稀釋，且隨後經由矽藻土過濾，同時用EtOAc (約400 mL)洗滌。分離各層，且洗滌(800 mL H2 O)有機層，乾燥(Na2 SO4 )，過濾且加以濃縮(73.88 g)。取乾殘餘物加至矽膠上且藉由矽膠層析法(20%至60% EtOAc/己烷)純化，得到呈米色固體狀之3-(1-環丙基-1H-吡唑-4-基)苯胺(31.5 g，82%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.03 (s, 1H), 7.66 (d, 1H), 6.97 (t, 1H), 6.73-6.72 (m, 1H), 6.71-6.68 (m, 1H), 6.42-6.38 (m, 1H), 5.00 (s, 2H), 3.75-3.68 (m, 1H), 1.08-1.00 (m, 2H), 1.00-0.92 (m, 2H)；LCMS: 200.3 [M+H]+ 。 遵循針對中間物 4 所述之程序由合適芳基鹵化物及合適
Figure 107108918-A0304-12-0030-1
酸/酯合成以下中間物。
Figure AA13
Figure AA14
 1 使用4-溴吡啶-2-胺。2 使用4-溴-6-甲基吡啶-2-胺。中間物 5 3 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯胺
Figure 02_image281
步驟 1 ： 3 - 甲基 - 1 -( 3 - 硝苯 )- 1H - 吡唑 將1-氟-3-硝基苯(2.00 g，14.17 mmol)、3-甲基-1H -吡唑(2.33 g，28.34 mmol)、K2 CO3 (1.96 g，14.17 mmol)及DMSO (20 mL)之混合物加熱至120℃隔夜。過濾反應混合物，且藉由RP-HPLC[水(10 mM NH4 HCO3 )-MeCN]純化過濾物，得到呈淡黃色固體狀之3-甲基-1-(3-硝苯)-1H -吡唑(2.0 g，69%)。1 H NMR (400 MHz, CDCl3 ): δ: 8.50 (t, 1H), 7.99-8.14 (m, 2H), 7.91 (d, 1H), 7.60 (t, 1H), 6.32 (d, 1H), 2.39 (s, 3H)；LCMS: 203.9 [M+H]+ 。步驟 2 ：3 -( 3 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯胺 在N2 下將鈀/碳(10 wt.%，50 mg，0.047 mmol)添加至3-甲基-1-(3-硝苯)-1H -吡唑(1.0 g，4.92 mmol)於MeOH (5 mL)中之溶液中。用3次真空/H2 循環使混合物脫氣，在室溫下在H2 (15 psi)下攪拌2小時，過濾，且高真空濃縮，得到呈淡黃色油狀之3-(3-甲基-1H -吡唑-1-基)苯胺(400 mg，粗物質)。1 H NMR (400 MHz, CDCl3 ): δ: 7.77 (d, 1H), 7.18 (t, 1H), 7.07 (t, 1H), 6.95 (dd, 1H), 6.56 (dd, 1H), 6.22 (d, 1H), 3.81 (s, 2H), 2.37 (s, 3H)；LCMS: 174.1 [M+H]+ 。中間物 6 3 - 碘 - N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 ) 苯胺
Figure 02_image283
在室溫下在N2 下將三乙醯氧基硼氫化鈉(3.74 g，17.6 mmol)添加至中間物 1 (2.56 g，11.0 mmol)、3-碘苯胺(2.56 g，11.7 mmol)、乙酸(1.3 mL，23 mmol)及二氯乙烷(45 mL)之溶液中。攪拌反應持續80分鐘，倒入50 mL飽和NaHCO3 中且用50 mL EtOAc萃取。用50 mL飽和NaHCO3 洗滌EtOAc層且用50 mL鹽水洗滌。合併水層且用25 mL EtOAc反萃取。乾燥(Na2 SO4 )經合併之有機物，過濾，濃縮且藉由矽膠層析法(0%至5% EtOAc/己烷)純化，得到呈黃色油狀之3-碘-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)苯胺(4.43 g，88%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 7.01-6.95 (m, 2H), 6.91 (s, 1H), 6.86-6.77 (m, 3H), 6.57 (d, 1H), 5.92 (t, 1H), 3.73 (s, 3H), 2.85 (t, 2H), 2.42-2.31 (m, 1H), 2.11 (s, 3H), 1.94-1.85 (m, 2H), 1.82-1.73 (m, 2H), 1.63-1.50 (m, 1H), 1.45-1.31 (m, 2H), 1.14-1.00 (m, 2H)；LCMS: 436.4 [M+H]+ 。中間物 7 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 )- N -(( 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 雙環 [ 2 . 2 . 2 ] 辛 - 1 - 基 ) 甲基 ) 苯胺
Figure 02_image285
在N2 下在冰/水浴中冷卻二氯乙烷。在0℃下將中間物 3 (151 mg，0.58 mmol)、中間物 4 (118 mg，0.59 mmol)，且隨後將三乙醯氧基硼氫化鈉(198 mg，0.93 mmol)添加至反應中。將反應升溫至室溫，在室溫下攪拌85分鐘，倒入20 mL飽和NaHCO3 中，且隨後用20 mL EtOAc萃取。用20 mL鹽水洗滌有機層，乾燥(Na2 SO4 )，過濾，濃縮且藉由矽膠層析法(10%至30% EtOAc/己烷)純化，得到呈白色泡沫狀之3-(1-環丙基-1H -吡唑-4-基)-N -((4-(4-甲氧基-3-甲基苯基)雙環[2.2.2]辛-1-基)甲基)苯胺(233 mg，90%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.09 (s, 1H), 7.71 (s, 1H), 7.11-7.05 (m, 2H), 7.00 (t, 1H), 6.84-6.76 (m, 2H), 6.68 (d, 1H), 6.47 (d, 1H), 5.32 (t, 1H), 3.75-3.68 (m, 4H), 2.83 (d, 2H), 2.12 (s, 3H), 1.78-1.69 (m, 6H), 1.62-1.52 (m, 6H), 1.10-1.04 (m, 2H), 1.00-0.93 (m, 2H)；LCMS: 442.3 [M+H]+ 。遵循針對中間物 6 及中間物 7 所述之程序由合適胺(SM或中間物)及合適醛中間物合成以下中間物。
Figure AA15
Figure AA16
Figure AA17
Figure AA18
Figure AA19
 1 替代條件：NaBH3 CN、AcOH、MeOH，室溫，隔夜；2 溶劑為DCM。中間物 8 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 ) 環己烷甲醯氯
Figure 02_image361
步驟 1 ：下午 07:51 2018/12/9 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 ) 環己烷甲酸第三丁基二甲基矽烷酯 在室溫下在N2 下將第三丁基二甲基氯矽烷(31.47 g，208.8 mmol)添加至反-4-羥基-環己烷甲酸(10.03 g，69.57 mmol)、咪唑(18.96 g，278.5 mmol)及DMF (140 mL)中(反應放熱至32℃)。在室溫下攪拌反應2小時，且隨後用300 mL乙醚稀釋。用1 N HCl (2 × 300 mL)洗滌有機層，用300 mL鹽水洗滌，乾燥(Na2 SO4 )，過濾且濃縮，得到呈透明油狀之反-4-((第三丁基二甲基矽烷基)氧基)環己烷甲酸第三丁基二甲基矽烷酯(31.5 g)。1 H NMR (400 MHz, DMSO-d 6 ): δ 3.61-3.53 (m, 1H), 2.26-2.18 (m, 1H), 2.04-1.96 (m, 2H), 1.92-1.85 (m, 2H), 1.51-1.39 (m, 2H), 1.39-1.27 (m, 2H), 0.94 (s, 9H), 0.89 (s, 9H), 0.26 (s, 6H), 0.06 (s, 6H)。步驟 2 ： 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 ) 環己烷甲酸 在室溫下在N2 下將碳酸鉀(58.01 g，419.7 mmol)之水溶液(300 mL)添加至反-4-((第三丁基二甲基矽烷基)氧基)環己烷甲酸第三丁基二甲基矽烷酯(31.5 g粗物質，69.6 mmol)、乙醇(1000 mL)及THF(300 mL)之混合物中。在室溫下攪拌反應3小時，濃縮直至剩餘300 mL為止，用600 mL鹽水稀釋，且隨後用20% NaHSO4 (550 mL)酸化至pH 2至pH 3。用800 mL乙醚萃取水層。用800 mL鹽水洗滌有機層，乾燥(Na2 SO4 )，過濾且濃縮，得到呈白色固體狀之反-4-((第三丁基二甲基矽烷基)氧基)環己烷甲酸(17.3 g，歷經2個步驟呈96%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 12.30 (br s, 1H), 3.59-3.51 (m, 1H), 2.15-2.05 (m, 1H), 1.88-1.74 (m, 4H), 1.41-1.29 (m, 2H), 1.28-1.16 (m, 2H), 0.84 (s, 9H), 0.02 (s, 6H)。步驟 3 ： 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 ) 環己烷甲醯氯 將(氯亞甲基)二甲基氯化亞銨(34.02 g，265.78 mmol)稱入於1000 mL圓底燒瓶(3頸)中且用真空/N2 循環(3×)脫氣。將甲苯(240 mL)添加至燒瓶中，且在冰浴中冷卻(1.3℃)混合物。將無水碳酸鉀* (68.71 g，497.14 mmol)及反-4-((第三丁基二甲基矽烷基)氧基)環己烷甲酸(34.29 g，132.69 mmol)依序添加至反應中。移除冰浴，且攪拌混合物持續35分鐘。將矽藻土(7 g)添加至反應中，且隨後經由矽藻土(70 g，Chemglass 465 mL燒結漏斗)過濾反應，且用甲苯(3 × 100 mL)洗滌。此溶液(451 g，8.5%酸氯化物，100%產率，72 mg/mL)直接用於醯化反應中。1 H NMR (400 MHz, CDCl3 ): δ 3.77-3.68 (m, 1H), 2.83-2.74 (m, 1H), 2.31-2.22 (m, 2H), 2.09-1.99 (m, 2H), 1.76-1.63 (m, 2H), 1.54-1.42 (m, 2H), 1.02 (s, 9H), 0.20 (s, 6H)。 *藉由用空氣加熱槍加熱持續約5分鐘而在真空下乾燥碳酸鉀，且隨後使其冷卻隔夜。 遵循針對中間物 8 所述之程序由合適起始物質合成以下中間物。
Figure AA20
 1 僅步驟3。2 步驟1：4-側氧基環己烷甲酸乙酯、AlMe3 、甲苯，0℃，1小時，產生呈順式/反式混合物形式之4-羥基-4-甲基環己烷甲酸乙酯；步驟2：TBSOTf、2,6-二甲基吡啶、DCM，0 ℃至室溫，隔夜；步驟3：LiOH·H2 O、H2 O、THF；步驟4：針對中間物8之步驟3。中間物 9 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 )- N -( 3 - 碘苯基 )- N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 ) 環己烷甲醯胺
Figure 02_image371
將中間物 8 (74 mg/mL於甲苯中，43 mL，11.49 mmol)添加至中間物 6 (3.32 g，7.63 mmol)、吡啶(2.5 mL，31 mmol)及甲苯(15 mL)之溶液中。在室溫下攪拌混合物90分鐘，用EtOAc (50 mL)稀釋，且加以洗滌(50 mL H2 O，50 mL飽和NaHCO3 ，且隨後50 mL鹽水)。乾燥(Na2 SO4 )有機層，過濾，濃縮，且藉由矽膠層析法(0%至10% EtOAc/己烷)純化，得到呈白色泡沫狀之反-4-((第三丁基二甲基矽烷基)氧基)-N -(3-碘苯基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(4.05 g，79%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 7.76 (d, 1H), 7.72 (s, 1H), 7.31 (d, 1H), 7.27 (t, 1H), 6.97-6.92 (m, 2H), 6.80-6.76 (m, 1H), 3.72 (s, 3H), 3.60-3.40 (m, 3H), 2.37-2.27 (m, 1H), 2.09 (s, 3H), 2.01-1.91 (m, 1H), 1.78-1.67 (m, 6H), 1.65-1.56 (m, 2H), 1.49-1.21 (m, 5H), 1.10-0.94 (m, 2H), 0.92-0.76 (m, 11H), -0.01 (s, 6H)；LCMS: 676.6 [M+H]+ 。 遵循針對中間物 9 所述之程序由合適中間物合成以下中間物。
Figure AA21
 1 所用替代條件：TEA、DCM，室溫，隔夜。中間物 10 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 )- N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 )- N -( 3 -( 4 , 4 , 5 , 5 - 四甲基 - 1 , 3 , 2 - 二氧硼㖦 - 2 - 基 ) 苯基 ) 環己烷甲醯胺
Figure 02_image379
用3次真空/N2 循環使雙(頻哪醇根基)二硼(1.42 g，5.59 mmol)、乙酸鉀(1.45 g，14.8 mmol)、Pd(dppf)Cl2 (135 mg，0.18 mmol)及甲苯(23 mL)之混合物脫氣。將中間物 9 (2.50 g，3.70 mmol)添加至混合物中，且用2次真空/N2 循環使反應脫氣，在115℃下加熱持續3.5小時，且隨後使其冷卻至室溫。用75 mL EtOAc稀釋混合物。用飽和NaHCO3 (2 × 75 mL)洗滌有機物，乾燥(Na2 SO4 )，過濾，濃縮，且高真空乾燥隔夜，得到呈褐色固體狀之反-4-((第三丁基二甲基矽烷基)氧基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N -(3-(4,4,5,5-四甲基-1,3,2-二氧硼㖦-2-基)苯基)環己烷甲醯胺(2.99 g，120%粗產物)。1 H NMR (400 MHz, CDCl3 ): δ 7.82-7.78 (m, 1H), 7.61-7.57 (m, 1H), 7.43 (t, 1H), 7.27-7.24 (m, 1H), 6.99-6.94 (m, 2H), 6.74 (d, 1H), 3.80 (s, 3H), 3.72-3.45 (m, 3H), 2.44-2.33 (m, 1H), 2.20 (s, 3H), 2.11-2.01 (m, 1H), 1.90-1.76 (m, 6H), 1.75-1.65 (m, 3H), 1.58-1.47 (m, 2H), 1.42-1.32 (m, 14H), 1.24-1.10 (m, 2H), 1.06-0.92 (m, 2H), 0.84 (s, 9H), 0.01 (s, 6H)；LCMS: 676.6 [M+H]+ 。附註：中間物 10 亦由中間物 9 之溴化物形式合成。中間物 11 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 )- N -( 3 - 乙炔基苯基 )- N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 ) 環己烷甲醯胺
Figure 02_image381
步驟 1 ： 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 )- N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 )- N -( 3 -(( 三甲基矽烷基 ) 乙炔基 ) 苯基 ) 環己烷甲醯胺 在N2 下將乙炔基(三甲基)矽烷(7.56 g，76.95 mmol，10.65 mL)、CuI (733 mg，3.85 mmol)及Pd(PPh3 )2 Cl2 (2.70 g，3.85 mmol)添加至中間物 9 (26 g，38.48 mmol)於Et3 N (260 mL)中之溶液中。在90℃下攪拌混合物6小時，冷卻至室溫，且隨後用乙酸乙酯(250 mL)稀釋。用250 mL H2 O洗滌混合物。乾燥(Na2 SO4 )有機層，過濾，且濃縮。藉由矽膠層析法(石油醚/乙酸乙酯= 20:1至5:1)純化粗物質，得到呈黃色油狀之反-4-((第三丁基二甲基矽烷基)氧基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N -(3-((三甲基矽烷基)乙炔基)苯基)環己烷甲醯胺(21.5 g，產率78%)。1 H NMR (400 MHz, CDCl3 ): δ 7.45-7.47 (m, 1H), 7.34-7.38 (m, 1H), 7.26-7.27 (m, 1H), 7.12-7.14 (m, 1H), 6.95-6.97 (m, 2H), 6.73-6.75 (m, 1H), 3.80 (s, 3H), 3.50-3.58 (m, 3H), 2.35-2.38 (m, 1H), 2.19 (s, 3H), 1.84-1.88 (m, 1H), 1.77-1.84 (m, 6H), 1.56-1.66 (m, 4H), 1.34-1.37 (m, 3H), 1.13-1.16 (m, 2H), 1.00-1.04 (m, 2H), 0.84 (s, 9H), 0.29 (s, 9H), 0.01 (s, 6H)；LCMS: 646.5 [M+H]+ 。步驟 2 ： 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 )- N -( 3 - 乙炔基苯基 )- N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 ) 環己烷甲醯胺 將氟化銨(2.87 g，77.39 mmol)添加至反-4-((第三丁基二甲基矽烷基)氧基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N -(3-((三甲基矽烷基)乙炔基)苯基)環己烷甲醯胺(10 g，15.48 mmol)於MeOH (100 mL)中之溶液中。在60℃下攪拌混合物1小時，且隨後加以濃縮。藉由矽膠層析法(石油醚/乙酸乙酯= 100/1至10:1)純化粗物質，得到呈黃色油狀之反-4-((第三丁基二甲基矽烷基)氧基)-N -(3-乙炔基苯基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(7.8 g，產率88%)。1 H NMR (400 MHz, CDCl3 ): δ 7.49-7.51 (m, 1H), 7.40-7.42 (m, 1H), 7.31 (s, 1H), 7.17-7.19 (m, 1H), 6.95-6.97 (m, 2H), 6.73-6.75 (m, 1H),3.80 (s, 3H), 3.50-3.60 (m, 3H), 3.17 (s, 1H), 2.38-2.41 (m, 1H), 2.20 (s, 3H), 1.86-1.89 (m, 1H), 1.77-1.85 (m, 6H), 1.61-1.66 (m, 4H), 1.34-1.37 (m, 3H), 1.14-1.17 (m, 2H), 1.00-1.04 (m, 2H), 0.84 (s, 9H), 0.01 (s, 6H)。中間物 12 ；針對中間物 1 . 04 之 SM 6- 氯 - 3 - 甲氧基 - 2 - 氰基吡啶
Figure 02_image383
步驟 1 ： 2 - 氰基 - 3 - 甲氧基吡啶 1 - 氧化物 3-在室溫下將氯過苯甲酸(90.8 g，447 mmol，純度85%)添加至3-甲氧基-2-氰基吡啶(50 g，373 mmol)於DCE (500 mL)中之溶液中。在65℃下加熱反應混合物隔夜，且隨後使其冷卻至室溫。用NaHCO3 (5 × 300 mL)洗滌混合物，經Na2 SO4 乾燥，過濾，濃縮，且隨後在石油醚/EtOAc = 5/1 (300 mL)中濕磨，得到呈黃色固體狀之2-氰基-3-甲氧基吡啶1-氧化物(50 g，89%)。1 H NMR (400MHz, CDCl3 ): δ 7.95 (d, 1H), 7.37 (t, 1H), 6.90 (d, 1H), 4.03 (s, 3H)；LCMS: 151.0 [M+H]+ 。步驟 2 ： 6 - 氯 - 3 - 甲氧基 - 2 - 氰基吡啶 在N2 下將2-氰基-3-甲氧基吡啶1-氧化物(30 g，200 mmol)及POCl3 (333 g，2.17 mol)之混合物加熱至100℃持續2小時。將混合物濃縮至乾燥，用NaHCO3 (300 mL)稀釋，且用EtOAc (2 × 100 mL)萃取。合併有機層，乾燥(Na2 SO4 )，過濾，濃縮，且隨後藉由矽膠層析法(石油醚/EtOAc = 2/1)純化，得到呈黃色固體狀之6-氯-3-甲氧基-2-氰基吡啶(20 g，59%)。1 H NMR (400MHz, CDCl3 ): δ 7.51 (d, 1H), 7.38 (d, 1H), 3.99 (s, 3H)；LCMS: 169.0 [M+H]+ 。中間物 13 ； 針對中間物 1 . 09 之 SM 5- 溴 - 1 - 甲基 - 1H - 吡咯并 [ 2 , 3 - c ] 吡啶
Figure 02_image385
在0℃下在N2 下將氫化鈉(3.65 g，91.36 mmol，純度60%)添加至5-溴-1H -吡咯并[2,3-c]吡啶(9 g，45.68 mmol)於DMF (100 mL)中之溶液中。攪拌反應持續0.5小時，且隨後在0℃下在N2 下逐滴添加Me2 SO4 (5.76 g，45.68 mmol)。將反應升溫至室溫持續2小時，倒入水(200 mL)中，且用EtOAc (5 × 100 mL)萃取。用水(2 × 100 mL)洗滌經合併之有機層，用鹽(100 mL)水洗滌，經Na2 SO4 乾燥，過濾，濃縮，且隨後藉由矽膠層析(石油醚/EtOAc = 4/1)純化，得到呈黃色固體狀之5-溴-1-甲基-1H -吡咯并[2,3-c]吡啶(9.6 g，99.5 %)。1 H NMR (400MHz, DMSO-d6 ): δ 8.64 (s, 1H), 7.73 (s, 1H), 7.63 (d, 1H), 6.47 (d, 1H), 3.89 (s, 3H)；LCMS: 211.0 [M+H]+ 。中間物 14 ； 針對中間物 1 . 03 之 SM 5- 溴 - 3 - 氟 - 1 - 甲基 - 1H - 吲唑
Figure 02_image387
在室溫下將四氟硼酸1-(氯甲基)-4-氟-1,4-二氮雙環[2.2.2]辛烷-1,4-二鎓(16.11 g，45.48 mmol)添加至5-溴-1-甲基-1H -吲唑(8.00 g，37.90 mmol)於CH3 CN (80 mL)中之溶液中。在80℃下攪拌混合物隔夜，在室溫下用H2 O (50 mL)淬滅，且隨後用EtOAc (50 mL)稀釋。用EtOAc (3 × 50 mL)萃取混合物。經Na2 SO4 乾燥經合併之有機層，過濾且減壓濃縮獲得殘餘物。藉由管柱層析(石油醚/乙酸乙酯= 50至5:1)純化殘餘物，得到呈白色固體狀之5-溴-3-氟-1-甲基-1H -吲唑(3.95 g，46%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 7.93 (s, 1H), 7.53-7.65 (m, 2H), 3.90 (s, 3H)。化合物 1 反 - 4 - 羥基 - N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 )- N -( 3 -( 4 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 ) 環己烷甲醯胺
Figure 02_image389
步驟 1 ： 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 )- N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 )- N -( 3 -( 4 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 ) 環己烷甲醯胺 將Cu2 O (2.6 mg，0.019 mmol)、Cs2 CO3 (241 mg，0.740 mmol)、水楊醛肟(10 mg，0.074 mmol)及4-甲基-1H -吡唑(45.5 mg，0.555 mmol)添加至中間物 9 (250 mg，0.370 mmol)於CH3 CN (10 mL)中之溶液中。在80℃下在N2 下攪拌所得混合物隔夜，使其冷卻至室溫,過濾且真空濃縮。藉由製備型TLC (PE/EA = 10/1)純化粗產物，得到呈淡黃色油狀之反-4-((第三丁基二甲基矽烷基)氧基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N -(3-(4-甲基-1H -吡唑-1-基)苯基)環己烷甲醯胺(100 mg，43%)。LCMS: 630.5 [M+H]+ 。步驟 2 ： 反 - 4 - 羥基 - N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 )- N -( 3 -( 4 - 甲基 - 1H - 吡唑 - 1 - 基 ) 苯基 ) 環己烷甲醯胺 將鹽酸水溶液(1 M，0.5 mL)添加至反-4-((第三丁基二甲基矽烷基)氧基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N -(3-(4-甲基-1H -吡唑-1-基)苯基)環己烷甲醯胺(80.0 mg，0.127 mmol)於MeOH (4 mL)中之溶液中。在室溫下攪拌混合物0.5小時，倒入10 mL冷水中，且隨後用5% MeOH/DCM (15 mL)萃取。用10 mL鹽水洗滌有機層，乾燥(Na2 SO4 )，過濾，濃縮，且藉由製備型TLC (PE/EA = 1/1)純化，得到呈白色固體狀之反-4-羥基-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N -(3-(4-甲基-1H -吡唑-1-基)苯基)環己烷甲醯胺(21 mg，32%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.37 (s, 1H), 7.77-7.86 (m, 1H), 7.73 (s, 1H), 7.52-7.62 (m, 2H), 7.20 (d, 1H), 6.92-6.96 (m, 2H), 6.78 (d, 1H), 4.35-4.42 (m, 1H), 3.72 (s, 3H), 3.54-3.61 (m, 2H), 3.26-3.30 (m, 1H), 2.00-2.12 (m, 7 H), 1.69-1.80 (m, 6H), 1.59-1.68 (m, 2H), 1.22-1.49 (m, 6H), 0.99-1.12 (m, 2H), 0.70-0.85 (m, 2H)；LCMS: 516.2 [M+H]+ 。化合物 2 反 - N -(( 反 - 4 -( 3 - 氰基 - 4 - 甲氧苯基 ) 環己基 ) 甲基 )- N -( 3 -( 1 - 乙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- 4 - 羥基環己烷甲醯胺
Figure 02_image391
步驟 1 ： 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 )- N -(( 反 - 4 -( 3 - 氰基 - 4 - 甲氧苯基 ) 環己基 ) 甲基 )- N -( 3 -( 1 - 乙基 - 1H - 吡唑 - 4 - 基 ) 苯基 ) 環己烷甲醯胺 用3次真空/N2 循環使中間物 9 . 01 (101 mg，0.15 mmol)、(1-乙基-1H -吡唑-4-基)
Figure 107108918-A0304-12-0030-1
酸(33 mg，0.24 mmol)、Pd(dppf)Cl2 (15 mg，0.02 mmol)、二噁烷(1.5 mL)及0.4 M K2 CO3 (1.1 mL，0.44 mmol)之混合物脫氣，在80℃下攪拌25分鐘，使其冷卻至室溫，倒入20 mL飽和NaHCO3 中，且隨後用20 mL EtOAc萃取。用20 mL鹽水洗滌有機物，乾燥(Na2 SO4 )，過濾，濃縮，且藉由矽膠層析法(20%至50%乙酸乙酯之己烷溶液)純化，得到反-4-((第三丁基二甲基矽烷基)氧基)-N -((反-4-(3-氰基-4-甲氧苯基)環己基)甲基)-N -(3-(1-乙基-1H -吡唑-4-基)苯基)環己烷甲醯胺(79 mg，81%)。LCMS: 655.5 [M+H]+ 。步驟 2 ： 反 - N -(( 反 - 4 -( 3 - 氰基 - 4 - 甲氧苯基 ) 環己基 ) 甲基 )- N -( 3 -( 1 - 乙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- 4 - 羥基環己烷甲醯胺 在0℃下將鹽酸水溶液(1 N，0.17 mL，0.17 mmol)添加至反-4-((第三丁基二甲基矽烷基)氧基)-N -((反-4-(3-氰基-4-甲氧苯基)環己基)甲基)-N -(3-(1-乙基-1H -吡唑-4-基)苯基)環己烷甲醯胺(79 mg，0.12 mmol)、甲醇(0.5 mL)及四氫呋喃(0.5 mL)之溶液中。將反應升溫至室溫，在室溫下攪拌1小時，倒入20 mL低溫飽和NaHCO3 中，且隨後用20 mL EtOAc萃取。用20 mL飽和NaHCO3 洗滌有機物且用20 mL鹽水洗滌。用20 mL EtOAc反萃取經合併之水層。乾燥(Na2 SO4 )經合併之萃取物，過濾，濃縮，且藉由矽膠層析法(0%至7%甲醇之DCM溶液)純化，得到呈黃色泡沫狀之反-N -((反-4-(3-氰基-4-甲氧苯基)環己基)甲基)-N -(3-(1-乙基-1H -吡唑-4-基)苯基)-4-羥基環己甲醯胺(60 mg，92%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.29 (s, 1H), 7.94 (s, 1H), 7.59 (d, 1H), 7.56-7.48 (m, 3H), 7.45 (t, 1H), 7.15-7.06 (m, 2H), 4.39 (d, 1H), 4.15 (q, 2H), 3.86 (s, 3H), 3.66-3.46 (m, 2H), 3.32-3.20 (m, 1H), 2.49-2.40 (m, 1H), 2.11-2.00 (m, 1H), 1.81-1.68 (m, 6H), 1.68-1.59 (m, 2H), 1.48-1.27 (m, 8H), 1.12-0.99 (m, 2H), 0.82-0.68 (m, 2H)；LCMS: 541.4 [M+H]+ 。 遵循針對化合物 2 所述之程序由合適中間物及合適
Figure 107108918-A0304-12-0030-1
酸或
Figure 107108918-A0304-12-0030-1
酸酯合成以下化合物。
Figure AA22
Figure AA23
 替代條件：步驟1：1 1 M Na2 CO3 、DMF，50℃，2 Cs2 CO3 、DMF (1%至2%水)，50℃，3 Pd(PPh3 )4 、Cs2 CO3 、DMF (2%水)，50℃；步驟2：4 6 N HCl。化合物 3 反 - N -( 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- 4 - 羥基 - N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 ) 環己烷甲醯胺
Figure 02_image411
步驟 1 ： 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 )- N -( 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 ) 環己烷甲醯胺 用3次真空/N2 循環使4-溴-1-環丙基-1H -吡唑(65 mg，0.35 mmol)、中間物 10 (163 mg，0.20 mmol)、Cs2 CO3 (196 mg，0.60 mmol)、Pd(dppf)Cl2 、DMF (2 mL)及H2 O (20 µL)之混合物脫氣，在80℃下加熱110分鐘，且使其冷卻至室溫。將反應倒入20 mL飽和NaHCO3 中，且隨後用EtOAc (2 × 20 mL)萃取。用20 mL鹽水洗滌經合併之有機物，乾燥(Na2 SO4 )，過濾，濃縮，且藉由矽膠層析法(10%至30%乙酸乙酯之己烷溶液)純化，得到呈白色泡沫狀之反-4-((第三丁基二甲基矽烷基)氧基)-N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(63 mg，48%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 7.93 (s, 1H), 7.61 (d, 1H), 7.56-7.52 (m, 1H), 7.43 (t, 1H), 7.08 (d, 1H), 6.98-6.91 (m, 2H), 6.81-6.75 (m, 1H), 3.77-3.69 (m, 4H), 3.64-3.45 (m, 3H), 2.38-2.28 (m, 1H), 2.13-2.02 (m, 4H), 1.81-1.68 (m, 6H), 1.68-1.59 (m, 2H), 1.51-1.36 (m, 3H), 1.36-1.22 (m, 2H), 1.12-0.95 (m, 6H), 0.89-0.74 (m, 11H), -0.03 (s, 6H)；LCMS: 656.6 [M+H]+ 。步驟 2 ： 反 - N -( 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- 4 - 羥基 - N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 ) 環己烷甲醯胺 在0℃下將鹽酸水溶液(6 N，0.13 mL，0.78 mmol)添加至反-4-((第三丁基二甲基矽烷基)氧基)-N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(62 mg，0.095 mmol)、甲醇(0.5 mL)及四氫呋喃(0.5 mL)之溶液中。將反應升溫至室溫，攪拌40分鐘，倒入20 mL低溫飽和NaHCO3 中，且隨後用EtOAc萃取。用20 mL飽和NaHCO3 洗滌有機物且用20 mL鹽水洗滌。用20 mL EtOAc反萃取第一含水洗滌液。乾燥(Na2 SO4 )經合併之萃取物，過濾，濃縮，且藉由矽膠層析法(0%至7% MeOH/DCM)純化，得到呈灰白色泡沫狀之反-N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-4-羥基-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(50 mg，98%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.56-7.51 (m, 1H), 7.44 (t, 1H), 7.09 (d, 1H), 6.98-6.92 (m, 2H), 6.81-6.75 (m, 1H), 4.39 (d, 1H), 3.78-3.69 (m, 4H), 3.63-3.48 (m, 2H), 3.30-3.20 (m, 1H), 2.38-2.28 (m, 1H), 2.09 (s, 3H), 2.08-1.99 (m, 1H), 1.80-1.68 (m, 6H), 1.67-1.58 (m, 2H), 1.48-1.37 (m, 3H), 1.32-1.20 (m, 2H), 1.11-0.95 (m, 6H), 0.81-0.67 (m, 2H)；LCMS: 542.5 [M+H]+ 。 遵循針對化合物 3 所述之程序由中間物 10 及合適芳基鹵化物合成以下化合物。
Figure AA24
Figure AA25
 替代條件：步驟1：1 K2 CO3 水溶液、二噁烷，80℃，0.5至5小時；步驟2：2 1N HCl。化合物 4 反 - 4 - 羥基 - N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 )- N -( 3 -(( 1 - 甲基 - 1H - 吡唑 - 4 - 基 ) 乙炔基 ) 苯基 ) 環己烷甲醯胺
Figure 02_image439
步驟 1 ： 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 )- N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 )- N -( 3 -(( 1 - 甲基 - 1H - 吡唑 - 4 - 基 ) 乙炔基 ) 苯基 ) 環己烷甲醯胺 在80℃下在N2 下攪拌中間物 11 (301 mg，0.525 mmol)、4-碘-1-甲基-1H -吡唑(131 mg，0.629 mmol)、CuI (10 mg，0.053 mmol)、Pd(PPh3 )2 Cl2 (37 mg，0.052 mmol)及Et3 N (5 mL)之混合物1小時，冷卻至室溫，倒入水(30 mL)中，且隨後用EtOAc (3 × 20 mL)萃取。用鹽水(2 × 20 mL)洗滌經合併之有機層，乾燥(Na2 SO4 )，過濾且減壓濃縮。藉由矽膠層析法(石油醚/乙酸乙酯= 25:1至5:1)純化殘餘物，得到呈黃色油狀之反-4-((第三丁基二甲基矽烷基)氧基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N -(3-((1-甲基-1H -吡唑-4-基)乙炔基)苯基)環己烷甲醯胺(115 mg，29%)。1 H NMR (400 MHz, CDCl3 ): δ 7.69 (s, 1H), 7.61 (s, 1H), 7.36-7.50 (m, 2H), 7.28-7.33 (m, 1H), 7.12 (d, 1H), 6.91-7.02 (m, 2H), 6.75 (d, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 3.48-3.65 (m, 3H), 2.35-2.43 (m, 1H), 2.20 (s, 3H), 2.05-2.14 (m, 1H), 1.77-1.90 (m, 8H), 1.49-1.73 (m, 8H), 1.25-1.42 (m, 3H), 1.11-1.22 (m, 2H), 0.97-1.09 (m, 2H), 0.81-0.89 (m, 9H)；LCMS: 654.3 [M+H]+ 。步驟 2 ： 反 - 4 - 羥基 - N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 )- N -( 3 -(( 1 - 甲基 - 1H - 吡唑 - 4 - 基 ) 乙炔基 ) 苯基 ) 環己烷甲醯胺 在0℃下將鹽酸水溶液(1 M，0.30 mL)添加至反-4-((第三丁基二甲基矽烷基)氧基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N -(3-((1-甲基-1H -吡唑-4-基)乙炔基)苯基)環己烷甲醯胺(111 mg，0.170 mmol)、MeOH (2 mL)及THF (2 mL)之溶液中。移除冰/水浴且使反應升溫至室溫。在室溫下攪拌混合物1小時，倒入飽和NaHCO3 (40 mL)中，用EtOAc (3 × 20 mL)萃取。用鹽水(2 × 20 mL)洗滌經合併之有機層，乾燥(Na2 SO4 )，過濾且減壓濃縮。藉由RP-HPLC[水(10 mM NH4 HCO3 )-MeCN]純化殘餘物，得到呈白色固體狀之反-4-羥基-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N -(3-((1-甲基-1H -吡唑-4-基)乙炔基)苯基)環己烷甲醯胺(47.8 mg，52%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.09 (s, 1H), 7.71 (s, 1H), 7.48-7.52 (m, 2H), 7.42 (s, 1H), 7.32 (s, 1H), 6.93-6.95 (m, 2H), 6.72-6.83 (m, 1H), 4.34-4.47 (m, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 3.51-3.61 (m, 2H), 3.30-3.32 (m, 1H), 2.24-2.38 (m, 1H), 2.09 (s, 3H), 1.90-2.01 (m, 1H), 1.67-1.79 (m, 6H), 1.55-1.67 (m, 2H), 1.21-1.49 (m, 5H), 0.97-1.12 (m, 2H), 0.70-0.84 (m, 2H)；LCMS: 540.3 [M+H]+ 。 遵循針對化合物 4 所述之程序由中間物 11 及合適鹵化物合成以下化合物。
Figure AA26
 化合物 5 反 - N -( 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- N -(( 反 - 4 -( 3 - 氟 - 1 - 甲基 - 1H - 吲唑 - 5 - 基 ) 環己基 ) 甲基 )- 4 - 羥基環己烷甲醯胺
Figure 02_image447
步驟 1 ： 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 )- N -( 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- N -(( 反 - 4 -( 3 - 氟 - 1 - 甲基 - 1H - 吲唑 - 5 - 基 ) 環己基 ) 甲基 ) 環己烷甲醯胺 將中間物 8 (75 mg/mL甲苯溶液，1.7 mL，0.461 mmol)添加至室溫水浴中的中間物 7 . 06 (130 mg，0.293 mmol)，吡啶(95 µL，1.17 mmol)及甲苯(2.5 mL)之溶液中。在室溫下攪拌混合物2小時，用EtOAc (20 mL)稀釋，洗滌(20 mL飽和NaHCO3 ，且隨後20 mL鹽水)，乾燥(Na2 SO4 )，過濾且濃縮。藉由矽膠層析法(0%至40% EtOAc/己烷)純化殘餘物，得到呈白色泡沫狀之反-4-((第三丁基二甲基矽烷基)氧基)-N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-N -((反-4-(3-氟-1-甲基-1H -吲唑-5-基)環己基)甲基)環己烷甲醯胺(184 mg，90%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.54 (s, 1H), 7.50 (dd, 1H), 7.48-7.41 (m, 2H), 7.36 (d, 1H), 7.10 (d, 1H), 3.86 (s, 3H), 3.77-3.70 (m, 1H), 3.68-3.42 (m, 3H), 2.61-2.52 (m, 1H), 2.13-2.02 (m, 1H), 1.84-1.75 (m, 4H), 1.75-1.68 (m, 2H), 1.68-1.59 (m, 2H), 1.54-1.33 (m, 5H), 1.14-1.03 (m, 4H), 1.02-0.92 (m, 2H), 0.90-0.72 (m, 11H), -0.03 (s, 6H)；LCMS: 684.2 [M+H]+ 。步驟 2 ： 反 - N -( 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- N -(( 反 - 4 -( 3 - 氟 - 1 - 甲基 - 1H - 吲唑 - 5 - 基 ) 環己基 ) 甲基 )- 4 - 羥基環己烷甲醯胺 在0℃下將鹽酸水溶液(1 N，0.5 mL，0.5 mmol)添加至反-4-((第三丁基二甲基矽烷基)氧基)-N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-N -((反-4-(3-氟-1-甲基-1H -吲唑-5-基)環己基)甲基)環己烷甲醯胺(180 mg，0.263 mmol)、THF(1 mL)及MeOH (1 mL)之溶液中。10分鐘之後，移除冰浴，且攪拌反應50分鐘。用EtOAc (20 mL)稀釋混合物，洗滌(2 × 20 mL飽和NaHCO3 ，且隨後20 mL鹽水)，乾燥(Na2 SO4 )，過濾且濃縮。藉由矽膠層析法(0%至5% MeOH/DCM)純化殘餘物，得到呈白色泡沫狀之反-N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-N -((反-4-(3-氟-1-甲基-1H -吲唑-5-基)環己基)甲基)-4-羥基環己甲醯胺(150 mg，100%，純度95%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.54 (s, 1H), 7.50 (dd, 1H), 7.48-7.41 (m, 2H), 7.36 (dd, 1H), 7.10 (d, 1H), 4.38 (d, 1H), 3.86 (s, 3H), 3.77-3.70 (m, 1H), 3.68-3.43 (m, 2H), 3.31-3.20 (m, 1H), 2.61-2.52 (m, 1H), 2.16-2.00 (m, 1H), 1.84-1.68 (m, 6H), 1.68-1.59 (m, 2H), 1.52-1.33 (m, 5H), 1.15-1.04 (m, 4H), 1.02-0.96 (m, 2H), 0.81-0.67 (m, 2H)；LCMS: 570.4 [M+H]+ 。 遵循針對化合物 5 所述之程序由合適中間物合成以下化合物。
Figure AA27
Figure AA28
Figure AA29
Figure AA30
Figure AA31
 替代條件：步驟1：1 溶劑為DCM；2 DMAP、吡啶，80℃；3 TEA、DCM，室溫；4 DMAP、TEA，80℃，1小時；步驟2：5 3 M HCl、THF、MeOH，45℃。6 TBS在醯化期間裂解。7 在純化化合物5.27期間分離。化合物 6 反 - N -( 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- 4 - 羥基 - N -(( 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 雙環 [ 2 . 2 . 2 ] 辛 - 1 - 基 ) 甲基 ) 環己烷甲醯胺
Figure 02_image513
步驟 1 ： 反 - 4 -(( 第三丁基二甲基矽烷基 ) 氧基 )- N -( 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- N -(( 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 雙環 [ 2 . 2 . 2 ] 辛 - 1 - 基 ) 甲基 ) 環己烷甲醯胺 在室溫下將中間物 8 (44 mg/mL甲苯溶液，2.5 mL，0.397 mmol)之溶液添加至中間物 7 (114 mg，0.258 mmol)、吡啶(0.1 mL，1.2 mmol)及DCM (2.0 mL)之溶液中。在室溫下攪拌混合物135分鐘，且添加額外中間物 8 (44 mg/mL甲苯溶液，0.5 mL，0.079 mmol)。攪拌混合物90分鐘，用EtOAc (20 mL)稀釋，洗滌(2 × 15 mL飽和NaHCO3 ，且隨後15 mL鹽水)，乾燥(Na2 SO4 )，過濾且濃縮。藉由矽膠層析法(0%至35% EtOAc/己烷)純化殘餘物，得到呈白色泡沫狀之反-4-((第三丁基二甲基矽烷基)氧基)-N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-N -((4-(4-甲氧基-3-甲基苯基)雙環[2.2.2]辛-1-基)甲基)環己烷甲醯胺(155 mg，88%)。LCMS: 682.5 [M+H]+ 。步驟 2 ： 反 - N -( 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- 4 - 羥基 - N -(( 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 雙環 [ 2 . 2 . 2 ] 辛 - 1 - 基 ) 甲基 ) 環己烷甲醯胺 在0℃下將鹽酸水溶液(1 M，0.5 mL，0.5 mmol)添加至反-4-((第三丁基二甲基矽烷基)氧基)-N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-N -((4-(4-甲氧基-3-甲基苯基)雙環[2.2.2]辛-1-基)甲基)環己烷甲醯胺(150 mg，0.220 mmol)、THF (1 mL)及MeOH (1 mL)之混合物中。攪拌反應持續1小時，用EtOAc (20 mL)稀釋，洗滌(2 × 20 mL飽和NaHCO3 ，且隨後20 mL鹽水)，乾燥(Na2 SO4 )，過濾且濃縮。藉由矽膠層析法(0%至5% MeOH/DCM)純化殘餘物，得到呈白色泡沫狀之反-N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-4-羥基-N -((4-(4-甲氧基-3-甲基苯基)雙環[2.2.2]辛-1-基)甲基)環己烷甲醯胺(109 mg，89%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 7.94 (s, 1H), 7.59 (s, 1H), 7.54 (d, 1H), 7.40 (t, 1H), 7.16 (d, 1H), 7.03-6.97 (m, 2H), 6.76 (d, 1H), 4.40 (s, 1H), 3.76-3.71 (m, 2H), 3.70 (s, 3H), 3.62-3.32 (m, 1H), 3.31-3.20 (m, 1H), 2.22-2.11 (m, 1H), 2.08 (s, 3H), 1.80-1.68 (m, 2H), 1.66-1.55 (m, 8H), 1.46-1.31 (m, 8H), 1.11-0.99 (m, 4H), 0.83-0.66 (m, 2H)；LCMS: 568.4 [M+H]+ 。 遵循針對化合物 6 所述之程序由合適中間物合成以下化合物。
Figure AA32
 替代條件：步驟1：1 DMAP及吡啶作為溶劑；2 50℃。化合物 7 反 - 4 - 胺基 - N -( 3 -( 1 - 異丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 ) 環己烷甲醯胺
Figure 02_image519
步驟 1 ： ( 反 - 4 -(( 3 -( 1 - 異丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 ) 胺甲醯基 ) 環己基 ) 胺基甲酸第三丁酯 在室溫下將中間物 8 . 02 (58 mg/mL於甲苯中，9 mL，2.006 mmol)添加至中間物 7 . 21 (418 mg，1.001 mmol)、吡啶(0.33 mL，4.08 mmol)及DCM (4 mL)之溶液中。在室溫下攪拌所得混合物60分鐘，用50 mL EtOAc稀釋，洗滌(50 mL H2 O，50 mL飽和NaHCO3 ，且隨後50 mL鹽水)，乾燥(Na2 SO4 )，過濾，且隨後濃縮。藉由矽膠層析法(10%至50% EtOAc/己烷)純化殘餘物，得到呈白色泡沫狀之(反-4-((3-(1-異丙基-1H -吡唑-4-基)苯基)((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)胺甲醯基)環己基)胺基甲酸第三丁酯(622 mg，96%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.32 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.55-7.52 (m, 1H), 7.44 (t, 1H), 7.09 (d, 1H), 6.98-6.92 (m, 2H), 6.81-6.75 (m, 1H), 6.53 (d, 1H), 4.56-4.44 (m, 1H), 3.71 (s, 3H), 3.68-3.35 (m, 2H), 3.20-3.00 (m, 1H), 2.38-2.28 (m, 1H), 2.12-2.00 (m, 4H), 1.80-1.62 (m, 8H), 1.50-1.21 (m, 20H), 1.13-0.98 (m, 2H), 0.89-0.79 (m, 2H)；LCMS: 665.5 [M+Na]+ 。步驟 2 ： 反 - 4 - 胺基 - N -( 3 -( 1 - 異丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- N -(( 反 - 4 -( 4 - 甲氧基 - 3 - 甲基苯基 ) 環己基 ) 甲基 ) 環己烷甲醯胺 在室溫下攪拌(反-4-((3-(1-異丙基-1H -吡唑-4-基)苯基)((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)胺甲醯基)環己基)胺基甲酸第三丁酯(617 mg，0.960 mmol)及三氟乙酸(20%於DCM中，10 mL)之溶液35分鐘，用DCM (50 mL)稀釋，且洗滌(2 × 50 mL飽和NaHCO3 ，且隨後50 mL鹽水)。乾燥(Na2 SO4 )有機層，過濾，且隨後濃縮得到呈白色泡沫狀之反-4-胺基-N -(3-(1-異丙基-1H -吡唑-4-基)苯基)-N -((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺(515 mg，99%)。1 H NMR (400 MHz, DMSO-d 6 ): δ 8.32 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.56-7.52 (m, 1H), 7.44 (t, 1H), 7.09 (d, 1H), 6.97-6.92 (m, 2H), 6.80-6.76 (m, 1H), 4.56-4.44 (m, 1H), 3.71 (s, 3H), 3.66-3.37 (m, 2H), 3.11-2.87 (m, 2H), 2.48-2.40 (m, 1H), 2.38-2.28 (m, 1H), 2.13-2.00 (m, 4H), 1.80-1.60 (m, 8H), 1.49-1.35 (m, 9H), 1.35-1.21 (m, 2H), 1.13-0.99 (m, 2H), 0.77-0.60 (m, 2H)；LCMS: 543.6 [M+H]+ 。 遵循針對化合物 7 所述之程序由中間物 7 合成以下化合物。
Figure AA33
 化合物 8 反 - N -( 3 -( 1 - 環丙基 - 1H - 吡唑 - 4 - 基 ) 苯基 )- 4 - 羥基 - N -(( 反 - 4 -( 4 - 羥基 - 3 - 甲基苯基 ) 環己基 ) 甲基 ) 環己烷甲醯胺
Figure 02_image523
在30℃下歷經2分鐘將BBr3 (4.0 mL，1M於DCM中)之溶液逐滴添加至化合物 3 (1.007 g，1.858 mmol)及無水DCM (40 mL)之溶液中。反應變得濃稠，伴有白色塊狀固體，且加以劇烈攪拌。6小時之後，添加額外DCM (5 mL)及BBr3 (1 mL)。24小時總反應時間之後，添加CH3 OH/H2 O混合物(20 mL，19:1)。濃縮反應，且隨後藉由矽膠層析法(1%至20% CH3 OH於DCM中)純化，得到含有二級胺之混合物(脫醯化)。藉由逆相HPLC(Waters SunFire管柱；55% CH3 CN/45% H2 O，含有0.1% TFA)純化此混合物，且用EtOAc (60 mL)稀釋濃縮溶離份且用飽和NaHCO3 (50 mL)洗滌。乾燥(MgSO4 )有機層，過濾，濃縮，且隨後保持在真空(0.1毫托)下持續數天，得到呈白色泡沫狀之反-N -(3-(1-環丙基-1H -吡唑-4-基)苯基)-4-羥基-N -((反-4-(4-羥基-3-甲基苯基)環己基)甲基)環己烷甲醯胺。1 H NMR (400 MHz, DMSO-d 6 ): d 8.92 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.53 (s, 1H), 7.44 (t, 1H), 7.08 (d, 1H), 6.85 (s, 1H), 6.77 (d, 1H), 6.63 (d, 1H), 4.38 (d, 1H), 3.78-3.71 (m, 1H), 3.55 (br, 2H), 3.32-3.21 (m, 1H), 2.33-2.23 (m, 1H), 2.06 (s, 3H), 2.08-1.99 (m, 1H), 1.79-1.67 (m, 6H), 1.67-1.58 (m, 2H), 1.48-1.33 (m, 3H), 1.33-1.20 (m, 2H), 1.10-0.95 (m, 6H), 0.81-0.68 (m, 2H)；LCMS: 528.4 [M+H]+ 。實例 A-1 ： 非經腸醫藥組合物 為了製備適用於藉由注射(皮下、靜脈內)投與之非經腸醫藥組合物，將1至1000 mg本文所述之化合物或其醫藥學上可接受之鹽或溶劑合物溶解於無菌水中，且隨後與10 mL之0.9%無菌生理鹽水混合。視情況添加適合緩衝液以及視情況選用之酸或鹼以調整pH。將混合物併入適用於藉由注射投與之單位劑型中。實例 A-2 ：口服溶液 為了製備用於口服遞送之醫藥組合物，將足夠量之本文所述之化合物或其醫藥學上可接受之鹽添加至水(伴隨視情況選用之增溶劑、視情況選用之緩衝液及味覺掩蔽賦形劑)中，得到20 mg/mL溶液。實例 A-3 ： 口服錠劑 藉由混合20至50重量%本文所述之化合物或其醫藥學上可接受之鹽、20至50重量%微晶纖維素、1至10重量%低取代之羥丙基纖維素及1至10重量%硬脂酸鎂或其他合適賦形劑製備錠劑。藉由直接壓縮製備錠劑。壓縮錠劑之總重量維持在100至500 mg。實例 A-4 ：口服膠囊 為了製備用於口服遞送之醫藥組合物，將10至500 mg本文所述之化合物或其醫藥學上可接受之鹽與澱粉或其他適合之粉末摻合物混合。將混合物併入適用於口服的諸如硬明膠膠囊之口服劑量單位中。 在另一實施例中，將10至500 mg本文所述之化合物或其醫藥學上可接受之鹽置放於4號膠囊或1號膠囊(羥丙甲纖維素或硬明膠)中且使膠囊閉合。實例 A-5 ： 表面凝膠組合物 為了製備醫藥表面凝膠組合物，使本文所述之化合物或其醫藥學上可接受之鹽與羥丙基纖維素、丙二醇、十四烷酸異丙酯及純化醇USP混合。隨後將所得凝膠混合物併入適用於表面投藥之諸如管之容器中。實例 B-1 ：活體外 FXR 分析 ( TK ) 接種 將CV-1細胞以2,000,000個細胞之密度接種於具有DMEM + 10%木炭雙汽提FBS之T175燒瓶中，且在37℃下在5% CO2 中培育持續18小時(O/N)。轉染 培育18小時之後，將T175燒瓶中之培養基更換為新製DMEM + 10%木炭超汽提血清。在聚丙烯試管中，針對hFXR、hRXR、TK-ECRE-luc及pCMX-YFP使2500 μL OptiMEM (Life Technologies，目錄號31985-062)與表現質體合併。隨後對試管進行短暫渦旋且在室溫下保溫5分鐘。將轉染劑(來自Roche之X-tremeGENE HP，目錄號06 366 236 001)添加至經渦旋之OptiMEM/質體混合物中，且在室溫下保溫持續20分鐘。保溫之後，將轉染劑/DNA混合物複合物添加至T175燒瓶中之細胞中，且在37℃下在5% CO2 中培育細胞持續18小時(O/N)。測試化合物 將化合物連續稀釋於DMSO中，且添加至經轉染之CV-1細胞中。隨後培育細胞持續18小時。次日，裂解細胞且進行螢光檢查。 本文所揭示之例示性化合物的代表性資料展現於下表中。表 2
Figure 107108918-A0304-0001
 其中『+++』意謂EC50 ≤0.25 μM；『++』意謂EC50 ＞ 0.25 μM且＜ 1 μM；『+』意謂EC50 ≥ 1 μM。 芬拉明(Fexarmine)對照組之最大功效＜ 25%之化合物歸類為『+』。實例 B-2 ： 活體外 FXR 分析 (hSHP) 接種 將CV-1細胞以2,000,000個細胞之密度接種於具有DMEM + 10%木炭雙汽提FBS之T175燒瓶中，且在37℃下在5% CO2 中培育持續18小時(O/N)。轉染 培育18小時之後，將T175燒瓶中之培養基更換為新製DMEM + 10%木炭超汽提血清。在聚丙烯試管中，針對hFXR、hRXR、hSHP-luc及pCMX-YFP使2500 μL OptiMEM (Life Technologies，目錄號31985-062)與表現質體合併。隨後對試管進行短暫渦旋且在室溫下保溫5分鐘。將轉染劑(來自Roche之X-tremeGENE HP，目錄號06 366 236 001)添加至經渦旋之OptiMEM/質體混合物中，且在室溫下保溫持續20分鐘。保溫之後，將轉染劑/DNA混合物複合物添加至T175燒瓶中之細胞中，且在37℃下在5% CO2 中培育細胞持續18小時(O/N)。測試化合物 將化合物連續稀釋於DMSO中，且添加至經轉染之CV-1細胞中。隨後培育細胞持續18小時。次日，裂解細胞且進行螢光檢查。實例 B-3 ： NASH 活性研究 ( STZ 模型 )藉由在出生之後2天單次皮下注射200 μg STZ，之後在4週齡之後隨意餵養高脂飲食(HFD)而在雄性C57BL/6中誘發NASH。繼續HFD的同時，可投配化合物持續4至8週以測定對NASH之作用。可在整個研究中用手持式葡萄糖計量測空腹葡萄糖。可藉由臨床化學分析儀量測血清丙胺酸轉胺酶(ALT)、天冬胺酸轉胺酶(AST)及三酸甘油酯(TG)。可使用三酸甘油酯E測試套組(日本東京之Wako)來量測肝臟組織中之TG含量。可在包埋於Tissue-TEK O.C.T.化合物中，急速冷凍於液氮中，且儲存於-80℃下之組織上進行肝臟切片之組織學分析。可切割出切片(5 μm)，風乾且固定於丙酮中。對於蘇木精及伊紅染色，可藉由波恩氏溶液(Bouin's solution)預固定肝臟切片，且隨後用蘇木精及伊紅溶液染色。可用天狼星紅染色(Sirius red staining)評定(區3)肝纖維化之程度。實例 B-4 ： NASH 活性研究 ( AMLN 模型 ) 藉由使用AMLN飲食(DIO-NASH) (D09100301，Research Diet，USA) (40%脂肪(18%反式脂肪)、40%碳水化合物(20%果糖)及2%膽固醇)進行飲食誘導而在雄性C57BL/6小鼠中誘發NASH。使動物之飲食保持29週。進行26週之飲食誘導之後，針對疾病進展(脂肪肝及纖維化)之基線組織學評定進行肝臟活組織檢查，根據肝纖維化期、脂肪變性評分及體重加以分級且隨機分入處理組中。活組織檢查之後三週，將小鼠分入處理組中且每日用FXR促效劑藉由經口管飼投配持續8週。在研究結束時，進行肝臟活組織檢查以藉由檢查分別用H&E及天狼星紅染色之組織切片來評定肝脂肪變性及纖維化。肝臟中之總膠原蛋白含量係藉由羥脯胺酸殘基之比色測定藉由膠原蛋白之酸水解進行量測。根據製造商之說明書，在使用自動分析儀Cobas C-111及商購套組(德國Roche Diagnostics)之單一測定中量測肝組織勻漿中之三酸甘油酯及總膽固醇含量。實例 B-5 ： CCl4 纖維化模型 可藉由每兩週利用腹膜內注射投與CCl4 而在BALB/c雄性小鼠中誘發纖維化。以1:1將CCl4 調配於油中且以1 ml/kg腹膜內注射。誘發纖維化2至4週之後，可每日藉由經口管飼投與化合物持續2至6週之處理，同時繼續投與CCl4 。在研究終止時，肝臟可經福馬林固定且用天狼星紅染色進行染色以供纖維化之組織病理學評估。可藉由羥脯胺酸殘基之比色測定藉由膠原蛋白之酸水解來量測總膠原蛋白含量。可藉由臨床化學分析儀量測血清丙胺酸轉胺酶(ALT)及天冬胺酸轉胺酶(AST)。實例 B-6 ： 肝內膽汁鬱積模型 嚙齒動物中由17a-炔雌醇(EE2)處理誘發的實驗性肝內膽汁鬱積為普遍使用的活體內模式，其用於檢查與雌激素誘發之膽汁鬱積有關的機制。可藉由每日皮下注射10 mg/kg 17a-炔雌醇(E2)持續5天而在成年雄性小鼠中誘發肝內膽汁鬱積。可藉由在E2誘發膽汁鬱積期間投與化合物來進行FXR配位體之測試。可藉由評定肝臟/體重比且量測血清總膽汁酸來對膽汁鬱積性作用進行定量，且可使用來自Diagnostic Chemicals公司之試劑及控制物及Cobas Mira plus CC分析儀(Roche Diagnostics)量測鹼性磷酸酶水準。對於組織學及有絲分裂量測，可將來自各小鼠之肝臟樣本固定於10%中性緩衝福馬林中。使用標準方案用蘇木精及伊紅染色載片且用顯微鏡針對結構性變化進行檢查。藉由Ki67之免疫組織化學染色評估肝細胞增殖。實例 B-7 ： 直接靶基因調節 可藉由用化合物以短期或長期任一者方式投配小鼠且在給藥後之不同時間點收集組織來評定FXR配位體對直接靶基因之調節。可自組織，諸如迴腸及肝臟分離RNA，且逆轉錄為cDNA以用於由FXR直接及間接調節的文獻中之已知基因，諸如SHP、BSEP、IBABP、FGF15、CYP7A1、CYP8B1及C3的定量PCR分析。實例 B-8 ： 小鼠 PK 研究 在向小鼠(CD-1、C57BL及飲食誘發之肥胖小鼠)單次靜脈內及口服投與大丸劑之後，量測作為測試製品的本文所揭示之化合物中之任一者的血漿藥物動力學。在DMSO、PEG400、羥丙基-β-環糊精(HPβCD)之媒劑溶液中調配測試製品以供靜脈內投藥且以選定劑量進行投與(例如以3 mL/kg之劑量體積)。在合適口服給藥媒劑(植物油、PEG400、Solutol、檸檬酸鹽緩衝液或羧甲基纖維素)中製備口服給藥調配物，且以選定劑量以5至10 mL/kg之劑量體積進行投與。藉由頰囊法在靜脈內或口服給藥後以預定時間間隔將血液樣本(大約0.15 mL)收集於含有EDTA之管中。藉由以10,000 g進行血液離心持續5分鐘來分離血漿，且將等分試樣轉移至96孔板中且在分析之前在-60℃或小於-60℃下儲存。 藉由用DMSO以一定濃度範圍稀釋DMSO儲備溶液來製備測試製品之校準標準物。將DMSO中的校準標準物之等分試樣與來自未處理小鼠之血漿合併以使得血漿中之校準標準物之最終濃度比DMSO中之校準標準物小10倍。將PK血漿樣本與空白DMSO合併以與基質匹配。將校準標準物及PK樣本與含有分析性內標物之冰冷乙腈合併且在4℃下以1850 g離心持續30分鐘。藉由LC/MS/MS分析上清液溶離份且對照校準曲線進行定量。使用Microsoft Excel(2013版)經由非室體模型分析計算藥物動力學參數(曲線下面積(AUC)、C最大 、T最大 、消除半衰期(T1 / 2 )清除率(CL)、穩態分佈體積(Vdss )及平均滯留時間(MRT))。實例 B-9 ： 大鼠 ANIT 模型 在一系列劑量(例如在0.01至100 mg/kg範圍內之劑量)內在膽汁鬱積之長期治療模型中評估本文所述之化合物。此模型用於評估使用FXR促效劑，例如本文所述之化合物來治療諸如以下之膽汁鬱積性肝臟病症的適用性：膽汁酸吸收障礙(例如原發性或繼發性膽汁酸腹瀉)、膽汁逆流性胃炎、膠原性結腸炎、淋巴球性結腸炎、改道性結腸炎(diversion colitis)、不確定性結腸炎、阿拉基症候群(Alagille syndrome)、膽道閉鎖、膽管消失性肝臟移植排斥、骨髓或幹細胞移植相關聯之移植物抗宿主疾病、囊腫性纖維化肝病及非經腸營養相關聯之肝病。 用食物中之α-萘基異硫氰酸酯(ANIT) (0.1% w/w)處理大鼠持續3天，之後用本文所述之化合物以一系列劑量(舉例而言，在0.01至100 mg/kg範圍內之劑量)處理。非膽汁鬱積性對照組餵養有不含ANIT之標準飲食且充當非膽汁鬱積性對照動物(「對照」)。口服給藥14天之後，針對分析物之水準分析大鼠血清。LLQ，定量之下限值。平均值± SEM；n = 5。 在大鼠血清中量測肝膽損傷指示物之水準，諸如升高的循環天冬胺酸轉胺酶(AST)、丙胺酸轉胺酶(ALT)、膽紅素及膽汁酸之水準。ANIT暴露誘發深度膽汁鬱積及肝細胞損傷。改良這些指示物中之多者的化合物適用於治療前述疾病或病狀。 肝臟中膽汁酸之積聚減少、膽道中膽汁酸分泌增強及抑制膽汁酸合成與FXR促效劑之藥理作用相一致。血清結合膽紅素(肝功能之直接指示物)之改良暗示利用經改良之膽汁分泌而自膽汁鬱積得到恢復。 此外，進行分析以確定本文所述之化合物對血清FGF15纖維母細胞生長因子15 (嚙齒動物中之FGF15；人類中之FGF19)表現、門靜脈血液中所分泌之激素及用於與SHP協同抑制CYP7A1表現的對肝臟之信號的影響。FGF15/19之直接FXR依賴性誘導連同FGF15/19之抗膽汁鬱積性使得其為用於偵測FXR促效劑之靶向參與的適宜血清生物標記物。 使用FGF15 Meso Scale Discovery (MSD)分析對血清FGF15水準進行定量。舉例而言，使用來自R&D Systems之小鼠FGF15抗體(AF6755)作為分析中之捕捉抗體及偵測抗體兩者。使用MSD SULFO-TAG NHS酯(MSD SULFO-TAG NHS-Ester)來標記FGF15抗體。用FGF15捕捉抗體塗佈MSD標準96孔板且用MSD阻斷劑A (R93AA-2)對板進行阻斷。用PBS + 0.05% Tween 20洗滌板之後，將MSD稀釋劑4施配於各孔中且培育30分鐘。將25 pi校準物稀釋液或樣本(血清或EDTA血漿)施配於各孔中且在室溫下震盪培育。 洗滌之後，添加偵測抗體且在室溫下震盪培育1小時。洗滌且添加MSD讀取緩衝液(R92TC-2)之後，在MSD SECTOR Imager 6000上讀取板。使用MSD資料分析軟體計算標準曲線及未知樣本之圖。 本文所述之實例及實施例僅為達成說明之目的且熟習此項技術者所提出之各種修改或變化將包括在本申請案之精神及範圍及隨附申請專利範圍之範疇內。實例 B-10 ：小鼠慢性 DSS 結腸炎模型 可使用慢性葡聚糖硫酸鈉(DSS)誘導之小鼠來測試對抗發炎性腸病(IBD)之化合物的治療潛力。慢性結腸炎可藉由在飲用水中向小鼠餵食DSS而誘導。舉例而言，飲用水中2% DSS持續5天及普通飲用水持續5天，隨後可分別以2.5%及3%之較高DSS濃度再重複此餵食循環兩次，持續總共三次循環。大約在第一次DSS餵食循環之後形成結腸炎，其可藉由體重減輕、大便堅實度及直腸出血來監測。可藉由在開始2% DSS水餵食之同時向小鼠投與FXR促效劑來測試FXR促效劑。或者，可在2% DSS水及普通水之第一次餵食循環後進行FXR促效劑之測試。在向小鼠投與FXR促效劑期間，可藉由對體重、大便堅實度及直腸出血之觀測來監測治療效應。安樂死之後，疾病形成及FXR促效劑之作用可藉由量測結腸重量及長度、針對黏膜中之炎症及結構性變化利用H&E染色之結腸組織學及與該疾病相關的基因之蛋白質及RNA表現得到進一步定量。實例 B-11 ： 授受性 T 細胞轉移結腸炎小鼠模型 授受性T細胞轉移結腸炎模型公認為人類發炎性腸病(IBD)之相關小鼠模型。為了在此模型中誘發結腸炎，自供體小鼠之脾臟分離CD4 T淋巴細胞群，隨後藉由使用流動式細胞測量術進行細胞分選來純化CD4+CD45RB高T細胞之亞群。將經純化之CD4+CD45RB高T細胞注射至接受SCID小鼠之腹膜腔中。T細胞轉移之後大約三至六週形成結腸炎，其可藉由體重減輕(但體重減輕量可為不同的)、大便不堅實或出血性腹瀉來監測。可在將經純化之CD4+CD45RB高T細胞注射至接受SCID小鼠的同時開始FXR促效劑之測試。或者，可在T細胞轉移後兩或三週，當結腸炎已在該模型中形成時投與FXR促效劑。在向小鼠投與FXR促效劑期間，可藉由對體重、大便堅實度及直腸出血之觀測來監測治療效應。安樂死之後，疾病形成及FXR促效劑之作用可藉由量測結腸重量及長度、針對黏膜中之炎症及結構性變化利用H&E染色之結腸及迴腸組織學及與該疾病相關的基因之蛋白質及RNA表現得到進一步定量。實例 B-12 ： Mdr1a -/- 小鼠模型 Mdr1a-/-小鼠模型為已用於測試人類IBD之新型療法的自發性結腸炎模型。此模型中Mdr1a基因之缺失會導致腸道障壁功能受損，引起腸道細菌之滲透增加且隨後引起結腸炎。在適當容納條件下，Mdr1a-/-小鼠可在約8至13週齡時罹患結腸炎。在疾病進展期間，對關於脫肛、大便堅實度及直腸出血之臨床觀測得分進行求和之疾病活動指數(DAI)可用於監測疾病。可在疾病之初始階段，一般伴隨DAI評分低於1.0時開始FXR促效劑之測試。或者,可在已罹患結腸炎，通常伴隨DAI評分大於2.0時開始投與FXR促效劑。可藉由量測DAI監測FXR促效劑之治療效應，且可在已達成所需疾病嚴重程度，一般伴隨DAI評分為約5.0時終止測試。安樂死之後，疾病形成及FXR促效劑之作用可藉由量測結腸重量及長度、針對黏膜中之炎症及結構性變化利用H&E染色之結腸組織學及與該疾病相關的基因之蛋白質及RNA表現得到進一步定量。 本文所述之實例及實施例僅為達成說明之目的且熟習此項技術者所提出之各種修改或變化將包括在本申請案之精神及範圍及隨附申請專利範圍之範疇內。CROSS REFERENCE This application claims the benefit of U.S. Provisional Patent Application Serial No. 62/471,517, filed March 15, 2017, which is hereby incorporated by reference in its entirety. The nuclear hormone receptor, farnesoid X receptor (also known as FXR or nuclear receptor subfamily 1, group H, member 4 (NR1H4)) (OMIM: 603826) acts as a regulator of bile acid metabolism. FXR is a ligand-activated transcriptional receptor expressed in various tissues including the adrenal gland, kidney, stomach, duodenum, jejunum, ileum, colon, gallbladder, liver, macrophages, and white and brown adipose tissue. FXR is highly expressed in tissues involved in bile acid metabolism, such as liver, intestine and kidney. Bile acids act as endogenous ligands for FXR such that enteric and systemic release of bile acids induces changes in FXR orientation in gene expression networks. Bile acids are the major oxidation products of cholesterol and, in some cases, regulators of cholesterol absorption after secretion in the intestine. The rate-limiting step in the conversion of cholesterol to bile acids is catalyzed by the cytochrome p450 enzyme, cholesterol 7-alpha-hydroxylase (CYP7A1), and takes place in the liver. The cytochrome p450 enzyme, sterol 12-alpha-hydroxylase (CYP8B1 ), mediates bile acid production and the relative amounts of two major bile acids, cholic acid and chenodeoxycholic acid, were determined. Activation of FXR can be achieved by increasing expression levels of hepatic small heterodimeric partner (SHP) (also known as nuclear receptor subfamily 0, group B, member 2; or NR0B2) and fibrils in mice Intestinal expression of blastogenic growth factor 15 (FGF15) and fibroblast growth factor 19 (FGF19) in humans to repress transcription of CYP7A1 and CYP8B1. SHP inhibits liver receptor homolog (LRH-1) and hepatocyte nuclear factor 4α (HNFa4), which are transcription factors that regulate CYP7A1 and CYP8B1 gene expression. Inhibition of CYP8B1 by FXR can be species-specific, and FXR activation can in some cases increase CYP8B1 expression in humans (Sanyal et al.PNAS ,2007 , 104, 15665). In some instances, FGF15/19 released from the gut subsequently activates fibroblast growth factor receptor 4 in the liver, resulting in activation of the mitogen-activated protein kinase (MAPK) signaling pathway that inhibits CYP7A1 and CYP8B1. In some embodiments, higher levels of bile acids are associated with insulin resistance. For example, insulin resistance sometimes results in decreased glucose absorption from the blood and increased nascent glucose production in the liver. In some cases, intestinal sequestration of bile acids has been shown to improve insulin resistance by promoting secretion of glucagon-like peptide-1 (GLP1 ) from intestinal L cells. GLP-1 is an incretin derived from the transcription product of the proglucagon gene. It is released in response to food intake and exerts control over appetite and gastrointestinal function and promotes insulin secretion from the pancreas. Biologically active forms of GLP-1 include GLP-1-(7-37) and GLP-1-(7-36)NH2 , which results from the selective cleavage of the proglucagon molecule. In such cases, activation of FXR results in reduced production of bile acids associated with reduced insulin resistance. In some embodiments, activation of FXR is also associated with secretion of pancreatic polypeptide folds, such as peptide YY (PYY or PYY3-36). In some instances, peptide YY is a gut hormone peptide that modulates neuronal activity in the hypothalamus and brainstem, brain regions involved in reward processing. In some instances, decreased PYY levels were associated with increased appetite and weight gain. In some instances, activation of FXR indirectly causes a reduction in plasma triglycerides. Clearance of triglycerides from the bloodstream is attributed to lipoprotein lipase (LPL). LPL activity is enhanced by the induction of its activator lipoprotein CII, and inhibition of its inhibitor lipoprotein CIII in the liver occurs after activation of FXR. In some instances, activation of FXR further modulates energy expenditure, such as adipocyte differentiation and function. Adipose tissue contains fat cells (adipocyte/fat cells). In some instances, the adipocytes further differentiate into brown adipose tissue (BAT) or white adipose tissue (WAT). The function of BAT is to generate body heat, while WAT acts as a fat storage tissue. In some instances, FXR is ubiquitously expressed in the intestine. In some instances, activation of FXR has been shown to induce the expression and secretion of FGF19 (or FGF15 in mice) in the intestine. FGF19 is a hormone that regulates bile acid synthesis and exerts effects on glucose metabolism, lipid metabolism and energy expenditure. In some instances, FGF19 has also been observed to regulate adipocyte function and differentiation. Indeed, studies have shown that administration of FGF19 to mice fed a high-fat diet increases energy expenditure, regulates adipocyte differentiation and function, reverses weight gain, and improves insulin resistance (see, Fu et al., "Fibroblast Growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes."Endocrinology 145 :2594-2603 (2004)). In some cases, intestinal FXR activity has also been shown to be associated with reduced microbial overgrowth, such as during feeding (Li et al., Nat Commun 4:2384, 2013). For example, studies have shown that activation of FXR is associated with several genes in the ileum, such asAng2 , iNos andIl18 associated with increased expression of genes with established antimicrobial effects. (Inagaki et al., Proc Natl Acad Sci USA 103:3920-3925, 2006). In some cases, barrier function and immunomodulatory effects of FXR in the intestine have been shown. FXR regulates the transcription of genes involved in bile salt synthesis, transport and metabolism in the liver and intestine and, in some cases, has been shown to cause amelioration of intestinal inflammation and prevent bacterial translocation in the intestine (Gadaleta et al.,Gut. 2011 Apr;60(4):463-72 ). In some instances, excessive production of bile acids or improper transport and recycling of bile acids can lead to diarrhea. FXR regulates the transcription of genes involved in the synthesis, transport and metabolism of bile salts in the liver and intestine and, in some cases, may cause diarrhea improvement Camilleri,Gut Liver. 2015 May; 9(3): 332-339 . G protein-coupled bile acid receptor 1 (also known as GPBAR2, GPCR19, bile acid or membrane receptor or M-BAR or TGR5) is a cell surface receptor for bile acids. Upon activation with bile acids, TGR5 causes the production of intracellular cAMP, which then triggers an increase in triiodothyronine due to activation of deiodinase (DIO2) in BAT, resulting in increased energy expenditure. Thus, in some embodiments, modulation of metabolic processes, such as bile acid synthesis, bile acid cycling, glucose metabolism, lipid metabolism, or insulin sensitivity is modulated by activating FXR. Furthermore, in some embodiments, dysregulation of metabolic processes, such as bile acid synthesis, bile acid cycling, glucose metabolism, lipid metabolism, or insulin sensitivity results in a metabolic disease, such as diabetes or diabetes-related conditions or disorders, alcoholic or Nonalcoholic liver disease or condition, intestinal inflammation, or cell proliferative disorder. In certain embodiments, disclosed herein are compounds that are active as FXR agonists. In some embodiments, the FXR agonists described herein are structurally distinct from bile acids, other synthetic FXR ligands, and other natural FXR ligands. In some embodiments, also disclosed herein are methods of treating or preventing metabolic disorders, such as diabetes, obesity, impaired glucose tolerance, dyslipidemia, or insulin resistance, by administering a therapeutically effective amount of an FXR agonist. In some instances, compounds are administered to the gastrointestinal tract of a subject. In other embodiments, disclosed herein are methods for treating or preventing alcoholic or nonalcoholic liver diseases or conditions (eg, via the gastrointestinal tract) by administering to a subject in need thereof a therapeutically effective amount of an FXR agonist Cholestasis, primary biliary cirrhosis, steatosis, cirrhosis, alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis ( PSC) or elevated liver enzymes). In other embodiments, disclosed herein includes methods for treating or preventing cholestasis, cirrhosis, primary biliary cirrhosis by administering a therapeutically effective amount of an FXR agonist to an individual in need thereof , nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD) or primary sclerosing cholangitis (PSC). In some embodiments, disclosed herein includes methods for treating or preventing cholestasis by administering a therapeutically effective amount of a FXR agonist to a subject in need thereof. In some embodiments, disclosed herein includes methods for treating or preventing primary biliary cirrhosis by administering a therapeutically effective amount of a FXR agonist to an individual in need thereof. In some embodiments, disclosed herein includes methods for treating or preventing NASH by administering a therapeutically effective amount of a FXR agonist to an individual in need thereof. In some embodiments, disclosed herein includes methods for treating or preventing NAFLD by administering a therapeutically effective amount of a FXR agonist to an individual in need thereof. In other embodiments, disclosed herein includes methods for treating or preventing inflammation and/or cell proliferation in the intestine by administering a therapeutically effective amount of a FXR agonist (e.g., via the gastrointestinal tract) to a subject in need thereof Sexual disorders, such as cancer methods. In yet other embodiments, the disclosures herein include modulating one or more of proteins or genes associated with metabolic processes, such as bile acid synthesis, glucose metabolism, lipid metabolism, or insulin sensitivity, such as increasing FGF19 (small FGF15) activity in mice, FXR agonists that increase secretion of GLP-1 or increase secretion of PYY.metabolic disease In certain embodiments, disclosed herein are methods of treating a metabolic disorder in an individual in need thereof. Also included herein are methods of preventing metabolic disorders in individuals in need thereof. In some instances, such methods comprise administering to a subject in need thereof a therapeutically effective amount of one or more of the compounds disclosed herein. In some instances, one or more compounds disclosed herein are absorbed in the gastrointestinal (GI) tract. In other instances, absorption of one or more of the disclosed compounds in the gastrointestinal tract activates FXR receptors, thereby treating or preventing a metabolic disorder in an individual. In some embodiments, disclosed compounds exhibit systemic exposure. In some cases, the disclosed compounds are exposed locally in the gut, but limited to the liver or limited to systemic exposure. In some embodiments, local exposure of the disclosed compounds in the gut can be manifested by modulation of FXR target genes in the gut. In some embodiments, target genes may include: SHP, FGF19 (FGF15), IBABP, C3, OST α/β. In some embodiments, about 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% of a disclosed compound is exposed in the gut , 99.5 % or higher than 99.5 %. In some instances, the disclosed compounds have about 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, or less than 50% exposure in the systemic circulation. In some embodiments, exposure of the FXR agonist to the intestinal lumen reduces the chance of side effects from systemic effects, thereby improving the safety profile of the therapy. In other embodiments, the disclosed compounds enhance FXR target gene expression in the gut. In other embodiments, the disclosed compounds further modulate gene expression in FXR-mediated pathways, such as FGF19 (FGF15), which inhibits CYP7A1 and CYP8B1 gene expression in the liver. In some instances, the disclosed compounds enhance gene expression in FXR-mediated pathways. In other instances, the disclosed compounds reduce or inhibit gene expression in FXR-mediated pathways. In some instances, gene expression in the gut, liver, kidney, or other tissue is enhanced by about 1%, 5%, 10%, 15%, 20%, 25%, relative to gene expression in the absence of a disclosed compound. 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 500%, 1,000%, 5,000%, 10,000%, 50,000%, 100,000%, 500,000% or higher than 500,000%. In some instances, gene expression in the gut, liver, kidney, or other tissue is reduced by about 100%, 90%, 80%, 70%, 60%, 50%, relative to gene expression in the absence of a disclosed compound. 40%, 30%, 25%, 20%, 15%, 10%, 5%, 1% or less than 1%. In some embodiments, the method substantially enhances FXR target gene expression in the gut while minimizing systemic plasma levels of the delivered compound. In some embodiments, the method substantially enhances FXR target gene expression in the gut and liver while minimizing systemic plasma levels of the delivered compound. In some embodiments, the method substantially enhances FXR target gene expression in the gut without substantially enhancing FXR target gene expression in the liver or kidney, while minimizing systemic plasma levels. In some embodiments, the method substantially enhances FXR target gene expression in the gut and liver and provides sustained systemic plasma levels of the delivered compound. In some embodiments, a metabolic disorder refers to any condition involving alterations in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or combinations thereof. In some instances, metabolic disorders are associated with deficiencies or excesses in metabolic pathways that result in imbalances in the metabolism of nucleic acids, proteins, lipids, and/or carbohydrates. Factors that affect metabolism include, but are not limited to, endocrine (hormone) control systems (such as the insulin pathway, enteroendocrine hormones including GLP-1, tomodulin, PYY, or the like) or neural control systems (such as GLP- 1). Exemplary metabolic disorders include, but are not limited to, diabetes, insulin resistance, dyslipidemia, liver disease, inflammation-related intestinal conditions, cell proliferative disorders, or the like.Diabetes and diabetes-related conditions or disorders In some embodiments, disclosed herein are methods of treating an individual suffering from diabetes or a diabetes-related condition or disorder utilizing the administration of an FXR agonist described herein. In some instances, the diabetes is type II diabetes or non-insulin-dependent diabetes mellitus (NIDDM). In some instances, the diabetes-related condition or disorder includes obesity, impaired glucose tolerance, dyslipidemia, and insulin resistance. In some instances, the diabetes-related condition or disorder further includes secondary complications, such as atherosclerosis, stroke, fatty liver disease, blindness, gallbladder disease, or polycystic ovarian disease. In some instances, an FXR agonist is administered to treat type II diabetes, obesity, impaired glucose tolerance, dyslipidemia, insulin resistance, or secondary complications such as atherosclerosis, stroke, fatty liver disease, blindness, Gallbladder disease or polycystic ovary disease. In some embodiments, the diabetic individual (e.g., type II diabetic individual) is further characterized by a body mass index (BMI) of 25 or greater, 30 or greater, 35 or greater, 40 or greater, such as a BMI of 25 to 29, 30 to 34 or 35 to 40. In some examples, the FXR agonists described herein reduce or prevent weight gain in a subject. In some instances, the weight gain is diet-induced weight gain. In other cases, the weight gain is non-diet-related, such as familial/genetic obesity or drug-induced obesity. In some examples, such methods reduce or prevent weight gain in an individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, weight gain is reduced or prevented from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some instances, the reduction or prevention of weight gain is relative to the reduction or prevention of weight gain observed in individuals not treated with the FXR agonist. Similarly, in some instances, an FXR agonist reduces the BMI of an individual. In some examples, such methods reduce the BMI of the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more relative to an individual not treated with the FXR agonist many. In some instances, the individual is overweight rather than obese. In other cases, the individual is neither overweight nor obese. In some instances, administration of a FXR agonist results in a decrease in the amount of serum lipids. In some examples, the amount of serum lipids is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60%, at least 70%, at least 75%, or more. In some instances, the amount of serum lipids is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, about 10% to about 70%, or about 10% to about 30%. In some instances, the reduction in the amount of serum lipids is relative to the amount of serum lipids observed in individuals not treated with the FXR agonist. In some examples, administration of a FXR agonist results in a decrease in triglyceride (eg, hepatic triglyceride) levels. In some instances, triglyceride (e.g., hepatic triglyceride) levels are reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60%, at least 70% , at least 75% or more. In some instances, triglyceride (e.g., hepatic triglyceride) levels are reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, about 10% to about 70% Or about 10% to about 30%. In some instances, the reduction in triglyceride (e.g., hepatic triglyceride) levels is relative to triglyceride (e.g., hepatic triglyceride) levels observed in individuals not treated with the FXR agonist . In some examples, administration of a FXR agonist results in increased insulin sensitivity to insulin in the liver. In some instances, insulin sensitivity is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, insulin sensitivity is increased by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, the increase in insulin sensitivity is relative to the sensitivity observed in individuals not treated with the FXR agonist. In some embodiments, administration of the FXR agonist results in a decrease in the amount of serum insulin in the individual. In some instances, serum insulin is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60%, at least 70%, at least 75%, or more. In some instances, serum insulin is decreased by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, about 10% to about 70%, or about 10% to about 30%. In some instances, the reduction in serum insulin levels is relative to levels observed in individuals not treated with the FXR agonist. In some embodiments, administration of a FXR agonist results in a decrease in the amount of serum glucose in the individual. In some examples, serum glucose is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60%, at least 70%, at least 75%, or more. In some instances, serum glucose is decreased by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, about 10% to about 70%, or about 10% to about 30%. In some instances, the reduction in serum glucose levels is relative to levels observed in individuals not treated with the FXR agonist. In some examples, an FXR agonist described herein increases browning of white adipose tissue in a subject. In some embodiments, the rate of browning of white adipose tissue is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, relative to individuals not treated with the FXR agonist. At least 50% or more. In some embodiments, administration of the FXR agonist does not result in substantial changes in food intake and/or fat consumption in the individual. In some instances, food intake and/or fat consumption is reduced, such as by less than 15%, less than 10%, or less than 5%. In some embodiments, there is no substantial change in appetite in the individual. In other embodiments, the subject's reported decrease in appetite is minimal. In some embodiments, administration of a FXR agonist results in an increase in metabolic rate in the individual. In some instances, an FXR agonist increases metabolic rate in a subject. In some instances, the metabolic rate in the individual is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75% Or more. In some instances, the metabolic rate is increased by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, about 10% to about 70%, or about 10% to about 30%. In some instances, the increase in metabolic rate is relative to the rate observed in individuals not treated with the FXR agonist. In some embodiments, increased metabolism is caused by enhanced oxidative phosphorylation in an individual, which in turn leads to increased energy expenditure by tissues, such as BAT. In such cases, FXR agonists help increase BAT activity. In some examples, BAT activity is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60%, at least 70%, at least 75%, or more. In some instances, BAT activity is increased by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, about 10% to about 70%, or about 10% to about 30%. In some instances, BAT activity is relative to BAT activity observed in individuals not treated with the FXR agonist.Alcoholic and nonalcoholic liver diseases or conditions Disclosed herein include the prevention and/or treatment of alcoholic or non-alcoholic liver diseases or conditions. Exemplary alcoholic or nonalcoholic liver diseases or conditions include, but are not limited to, cholestasis, cirrhosis, steatosis, alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD ), primary sclerosing cholangitis (PSC), elevated liver enzymes, and elevated triglyceride levels. In some embodiments, FXR agonists are used to prevent or treat alcoholic or non-alcoholic liver disease. In some embodiments, the FXR agonist is used to prevent or treat cholestasis, cirrhosis, steatosis, alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD) or primary Sexual sclerosing cholangitis (PSC).Cholestasis In some embodiments, the FXR agonists disclosed herein are used to treat cholestasis in a subject. Cholestasis, a decreased or stopped flow of bile, which in some cases can lead to liver toxicity due to the buildup of bile acids and other toxins in the liver. In some cases, cholestasis is a component of a variety of liver diseases, including cholestasis, cholestasis of pregnancy, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC ). In some cases, the blockage is due to gallstones, gallbladder trauma, drugs, one or more other liver diseases, or cancer. In some instances, enterohepatic circulation of bile acids enables absorption of fat and fat-soluble vitamins from the gut and allows elimination of cholesterol, toxins and metabolic by-products, such as bilirubin, from the liver. In some cases, activation of FXR induces expression of the microtubular bile transporters BSEP (ABCB11) and multidrug resistance-associated protein 2 (MRP2; ABCC2, cMOAT), and represses genes involved in bile acid biosynthesis, such as sterol 12α-Hydroxylase (CYP8B1) and CYP7A1. In some examples, the FXR agonist reduces cholestasis in the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, cholestasis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, the level of cholestasis is relative to the level of cholestasis in an individual not treated with the FXR agonist.primary biliary cirrhosis and liver cirrhosis In some embodiments, the FXR agonists disclosed herein are used to treat primary biliary cirrhosis (PBC) in an individual. PBC is a liver disease caused primarily by autoimmune damage to the bile ducts that transport bile acids (BA) outside the liver, leading to cholestasis. With the development of PBC, persistent toxic accumulation of BA can cause progressive liver damage. Chronic inflammation and fibrosis can develop into cirrhosis. In some examples, the FXR agonist reduces PBC in the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, the PBC is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, the level of PBC is relative to the level of PBC in an individual not treated with the FXR agonist. In some embodiments, the FXR agonists disclosed herein reduce cirrhosis in a subject. In some examples, the FXR agonist reduces cirrhosis in the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, cirrhosis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, the level of cirrhosis is relative to the level of cirrhosis in an individual not treated with the FXR agonist.Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis Nonalcoholic fatty liver disease (NAFLD) is associated with excess fat in the liver (steatosis) and, in some cases, progresses to NASH, which is defined by histological hallmarks of inflammation, cell death, and fibrosis. In some instances, primary NASH is associated with insulin resistance, while secondary NASH is caused by medical or surgical conditions or drugs such as, but not limited to, tamoxifen. In some cases, NASH progresses to advanced fibrosis, hepatocellular carcinoma, or end-stage liver disease requiring liver transplantation. In some instances, NASH results from a triglyceride (TG) imbalance. For example, dysfunctional adipocytes secrete pro-inflammatory molecules, such as cytokines and chemokines, leading to insulin resistance and loss of lipolysis inhibition in adipocytes. In some instances, failure of this lipolysis inhibition results in the release of free fatty acids (FFA) for circulation and uptake in the liver. In some instances, excessive accumulation of FFA in the triglyceride (TG) form in lipid droplets leads to oxidative stress, mitochondrial dysfunction, and upregulation of pro-inflammatory molecules. In some instances, activation of FXR inhibits triglyceride (TG)/fatty acid (FA) synthesis, which is promoted by inhibition of sterol regulatory element-binding protein 1c (SREBP1c) through activation of SHP. In some cases, FXR additionally increases TG clearance by stimulating lipoprotein lipase (LPL) activity, and increases residue and low Hepatic uptake of density lipoprotein. In some embodiments, the FXR agonists disclosed herein are used to treat non-alcoholic steatohepatitis (NASH). In some examples, the FXR agonist reduces NASH in the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, NASH is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, the level of NASH is relative to the level of NASH in an individual not treated with the FXR agonist. In some embodiments, the FXR agonists disclosed herein are used to treat NAFLD. In some examples, the FXR agonist reduces NAFLD in the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, NAFLD is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, the level of NAFLD is relative to the level of NAFLD in an individual not treated with the FXR agonist.fatty degeneration In some embodiments, the FXR agonists disclosed herein reduce fatty liver (steatosis) in an individual. In some examples, the FXR agonist reduces steatosis in the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, steatosis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, the level of steatosis is relative to the level of steatosis in an individual not treated with the FXR agonist.expand Enlargement of hepatocytes is characteristic of cell damage and is one of the characteristics of NASH. Enlargement is characteristic of progressive NAFL (types 3 and 4). The term applies to enlarged, swollen hepatocytes; affected cells are usually intermingled at areas of steatosis and in typical steatotic hepatitis, perivascular areas. Hepatocellular enlargement is most commonly seen with perisinusoidal fibrosis detectable by H&E. Enlarged hepatocytes are most easily seen when they contain MH (typical or poorly formed). Hepatocyte enlargement is a structural manifestation of microtubule disruption and severe cellular damage. In some embodiments, an FXR agonist disclosed herein reduces liver enlargement in a subject. In some examples, the FXR agonist reduces liver enlargement in the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, liver enlargement is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, liver enlargement is relative to the level of liver enlargement in individuals not treated with the FXR agonist.alcoholic hepatitis In some embodiments, the FXR agonists disclosed herein reduce alcoholic hepatitis in a subject. In some examples, the FXR agonist reduces alcoholic hepatitis in the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, the level of alcoholic hepatitis is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, the level of alcoholic hepatitis is relative to the level of alcoholic hepatitis in an individual not treated with the FXR agonist.primary sclerosing cholangitis In some embodiments, the FXR agonists disclosed herein are used to treat primary sclerosing cholangitis (PSC). PSC is a chronic and progressive cholestatic liver disease. PSC is characterized by progressive inflammation, fibrosis, and hepatic duct stricture formation. Common symptoms include itching and jaundice. The disease is largely associated with inflammatory bowel disease (IBD) - about 5% of patients with ulcerative colitis will have PSC. Up to 70% of patients with PSC also have IBD, most commonly ulcerative colitis.Other alcoholic and nonalcoholic liver diseases or conditions In some embodiments, the FXR agonists disclosed herein reduce liver enzymes in a subject. In some examples, the FXR agonist reduces liver enzymes (e.g., serum ALT and/or AST levels) in the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, At least 50% or more. In some instances, liver enzyme levels are decreased by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, liver enzyme levels are relative to liver enzyme levels in individuals not treated with the FXR agonist. In some embodiments, the FXR agonists disclosed herein reduce hepatic triglycerides in a subject. In some examples, the FXR agonist reduces hepatic triglycerides in the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, the level of hepatic triglycerides is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, hepatic triglyceride levels are relative to hepatic triglyceride levels in individuals not treated with the FXR agonist.inflammatory bowel disease Disclosed herein are methods of treating or preventing inflammatory bowel conditions. Exemplary inflammatory conditions include necrotizing enterocolitis (NEC), gastritis, ulcerative colitis, inflammatory bowel disease, irritable bowel disorder, pseudomembranous colitis, gastroenteritis, radiation-induced enteritis, chemotherapy-induced enteritis, gastro- Esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, gastrointestinal complications after bariatric surgery, gastric cancer, or after stomach or bowel resection of gastric cancer. In some embodiments, the inflammatory condition is NEC and the individual is a newborn or premature infant. In some embodiments, the individual is an enterally fed infant or a formula fed infant. In some embodiments, an FXR agonist disclosed herein is administered to an individual suffering from an inflammatory bowel condition. In some embodiments, an FXR agonist disclosed herein is administered to an individual suffering from necrotizing enterocolitis (NEC), gastritis, ulcerative colitis, inflammatory bowel disease, irritable bowel disorder, pseudomembranous Colitis, gastroenteritis, radiation-induced enteritis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, gastrointestinal after bariatric surgery Gastric complications, gastric cancer, or gastric cancer after gastrectomy or bowel resection. In some embodiments, an FXR agonist disclosed herein reduces intestinal inflammation in a subject, such as a human. In some examples, the FXR agonist reduces intestinal inflammation in the individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, intestinal inflammation is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, the level of intestinal inflammation is relative to the level of intestinal inflammation in an individual not treated with the FXR agonist.Gastrointestinal disease In certain embodiments, disclosed herein are methods of treating or preventing a gastrointestinal disorder in an individual in need thereof, the methods comprising administering to the individual a farnesoid X receptor (FXR) agonist as described herein. In some embodiments, the gastrointestinal disorder is irritable bowel syndrome (IBS), irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M), IBS unspecified (IBS-U) or bile acid diarrhea (BAD). Irritable bowel syndrome Irritable bowel syndrome (IBS) is a combination of symptoms including abdominal pain and changes in the pattern of bowel movements that persists over an extended period of time, usually years. The etiology of IBS remains unclear; however, problems with gut motility, food sensitivities, genetic factors, bacterial overgrowth of the small intestine, and problems with the gut-brain axis are thought to play a potential role. In some instances, IBS with diarrhea is classified as IBS with diarrhea (IBS-D). In some instances, IBS with constipation is classified as IBS with constipation (IBS-C). In some instances, IBS with alternating patterns of diarrhea and constipation is classified as mixed IBS (IBS-M). In some instances, IBS is not accompanied by either diarrhea or constipation and is classified as IBS unspecified (IBS-U). In some cases, IBS has four different variations: IBS-D, IBS-C, IBS-M, and IBS-U. In some embodiments, the symptoms of IBS are modeled by different pathologies. In some embodiments, sugar maldigestion, celiac disease, gluten intolerance without celiac disease, pancreatic exocrine insufficiency, small intestinal bacterial overgrowth, microscopic colitis, or bile acid malabsorption (BAM) mimics IBS- d. In some embodiments, pelvic floor achalasia (anismus), pelvic floor dyssynergia or puborectalis spasm or descending perineal syndrome mimics IBS-C. In some embodiments, the FXR agonists disclosed herein are used to treat IBS or any of its variants in a mammal. In some examples, the FXR agonist treatment reduces IBS symptoms in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. bile acid malabsorption Bile acid malabsorption (BAM), also known as bile acid diarrhea (BAD), bile acid-induced diarrhea, cholerheic enteropathy or choleretic enteropathy, or bile salt malabsorption, is The presence of bile acids in the colon can cause the condition of diarrhea. BAM is caused by a variety of conditions, such as Crohn's disease, cholecystectomy, celiac disease, radiation therapy, and pancreatic disease. In some cases, BAM is caused by drugs, such as metformin. In some embodiments, BAM is caused by overproduction of bile acids. Bile acid synthesis is adversely regulated by the ileal hormone fibroblast growth factor 19 (FGF-19); low levels of FGF-19 lead to increased bile acids. FXR activation promotes the synthesis of FGF-19, thereby reducing bile acid levels. In some embodiments, the FXR agonists disclosed herein are used to treat BAM in a mammal. In some embodiments, the FXR agonists disclosed herein reduce bile acid synthesis. In some embodiments, the FXR agonists disclosed herein reduce bile acid levels. In some embodiments, the FXR agonist and another therapeutic agent disclosed herein prevent BAD. In some examples, the FXR agonist reduces BAM symptoms in the mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more.graft versus host disease (GvHD) Graft versus host disease (GvHD) is a medical complication that arises after transplantation of tissues or cells from a histo-incompatible donor (ie, a genetically or immunologically different donor). Immune cells in the donor tissue or cells (graft) recognize the recipient (host) as foreign and attack. Non-limiting examples of transplanted tissues or cells that cause GvHD are blood preparations, stem cells such as bone marrow cells, and organs. There are different types of GvHD, depending on where the manifestation or symptoms occur: epidermal GvHD, hepatic GvHD, ocular GvHD, neuromuscular GvHD, urogenital GvHD, and gastrointestinal (GI) tract GvHD. Symptoms of gastrointestinal GvHD include dysphagia, odynophagia, weight loss, nausea, vomiting, diarrhea and/or abdominal cramps. Gastrointestinal GvHD causes mucosal shedding and severe intestinal inflammation. Inflammation of the biliary epithelium is suitably controlled by nuclear receptors such as glucocorticoid receptor (GR), FXR or peroxisome proliferator-activated receptor (PPAR). In some embodiments, the FXR agonists disclosed herein are used to treat GvHD or a complication of GvHD in a mammal. In some embodiments, the FXR agonists disclosed herein are used to treat gastrointestinal GvHD or a complication of gastrointestinal GvHD in a mammal. In some examples, the FXR agonist reduces gastrointestinal GvHD or complications of gastrointestinal GvHD in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more. In some instances, gastrointestinal GvHD or complications of gastrointestinal GvHD is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some embodiments, the FXR agonists disclosed herein reduce intestinal inflammation caused by GvHD of the gastrointestinal tract. In some embodiments, the FXR agonists disclosed herein reduce intestinal inflammation caused by gastrointestinal GvHD by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or From about 10% to about 30%.kidney disease In certain embodiments, disclosed herein are methods of treating or preventing kidney disease in an individual in need thereof, the methods comprising administering to the individual a farnesoid X receptor (FXR) agonist described herein. In some embodiments, kidney disease is associated with liver disease. In some embodiments, the kidney disease is associated with fibrotic liver disease. In some embodiments, renal disease is associated with metabolic liver disease. In some embodiments, renal disease is associated with metabolic conditions such as, but not limited to, diabetes, metabolic syndrome, NAFLD, insulin resistance, fatty acid metabolism disorders, and cholestasis. In some embodiments, the renal disease is diabetic nephropathy, renal disease associated with fibrosis, renal disease not associated with fibrosis, renal fibrosis, or any combination thereof. diabetic nephropathy Diabetic nephropathy is kidney disease characterized by damage to the glomeruli of the kidney. Diabetes promotes the overproduction of reactive oxygen species, which leads to nephrotic syndrome and glomerular scarring. As diabetic nephropathy progresses, the glomerular filtration barrier (GFB) is increasingly damaged, and as a result, proteins in the blood leak through this barrier and accumulate in Bowman's space. In some embodiments, the FXR agonists disclosed herein are used to treat diabetic nephropathy in a mammal. renal fibrosis Renal fibrosis is characterized by fibroblast activation and excessive deposition of extracellular matrix or connective tissue in the kidney, a hallmark of chronic kidney disease. FXR plays an important role in protection from renal fibrosis. Activation of FXR inhibits renal fibrosis and reduces accumulation of extracellular matrix proteins in the kidney. In some embodiments, the FXR agonists disclosed herein are used to treat renal fibrosis in a mammal. In one aspect, described herein is a method of treating or preventing a renal disease or condition in a mammal, the method comprising administering to the mammal an FXR agonist disclosed herein, or a pharmaceutically acceptable salt thereof, or solvates. In some embodiments, the renal disease or condition is diabetic nephropathy, renal disease associated with fibrosis, renal disease not associated with fibrosis, renal fibrosis, renal disease associated with metabolic disease, chronic kidney disease, polycystic Acute kidney disease, acute kidney disease, or any combination thereof.cell proliferative disease Further disclosed herein are methods of preventing or treating cell proliferative disorders, eg, in certain types of cancer. In some embodiments, the FXR agonists disclosed herein are used to prevent or treat adenocarcinoma or carcinoma derived from glandular tissue or in which tumor cells form recognizable glandular structures. In some embodiments, the adenocarcinoma is classified as papillary, alveolar based on the predominant pattern of cell arrangement, or as mucinous adenocarcinoma based on the specific products of the cells. In some cases, adenocarcinomas are observed, for example, in the colon, kidney, breast, cervix, esophagus, stomach, pancreas, prostate or lung. In some embodiments, the compounds disclosed herein are used to prevent or treat bowel cancer, such as colon cancer, for example, cancers that form in the tissue of the colon (the longest part of the large intestine), or another part of the intestine, such as the jejunum and/or ileum of cancer. Colon cancer is also called "colorectal cancer" in some cases. In some instances, the most common type of colon cancer is colon adenocarcinoma. In some instances, cancer progression is characterized by the stage or extent of cancer in the body. Staging is usually based on tumor size, the presence of cancer in lymph nodes, and the presence of cancer at sites other than the site of the primary cancer. The cancer stages of colon cancer include stage I, stage II, stage III and stage IV. In some embodiments, the colon adenocarcinoma is from any cancer stage. In other embodiments, the colon adenocarcinoma is a stage I cancer, a stage II cancer, or a stage III cancer. In some embodiments, an individual with stage I, stage II, stage III, or stage IV cancer is administered an FXR agonist described herein. In some embodiments, an individual with stage I, stage II, or stage III colon adenocarcinoma is administered an FXR agonist described herein. In some embodiments, the FXR agonists disclosed herein further reduce tumor burden in an individual. In some examples, the FXR agonist reduces tumor burden (such as colon tumor burden) in an individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or More. In some instances, tumor burden is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, the level of tumor burden is relative to the level of tumor burden in an individual not treated with the FXR agonist. In some instances, the FXR agonists disclosed herein further reduce tumor size and/or volume in an individual. In some instances, the FXR agonist reduces the size and/or volume of a tumor (such as a colon tumor) in an individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, At least 50% or more. In some instances, the tumor size is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, tumor size is relative to tumor size in an individual not treated with the FXR agonist. In other embodiments, the FXR agonists disclosed herein reduce the effects of tumor-induced cachexia in an individual. In some examples, the FXR agonist reduces the effect of cachexia (such as due to a colon tumor) in an individual by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more. In some instances, the effect of cachexia is reduced by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, the effect on cachexia is relative to the effect on cachexia in an individual not treated with the FXR agonist. In other embodiments, the FXR agonists disclosed herein increase the survival rate of individuals with tumors. In some instances, the FXR agonist increases survival in individuals with a tumor (such as colon cancer) by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, At least 50% or more. In some instances, survival is increased by about 5% to about 50%, about 5% to about 25%, about 10% to about 20%, or about 10% to about 30%. In some instances, survival is relative to survival in individuals not treated with the FXR agonist.compound The compounds described herein, including their pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates, are farnesoid X receptor agonists. In one aspect, described herein are farnesoid X receptor agonists and uses thereof. In one aspect, described herein is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image005
Formula (I) where, X1 for CH or N; R1 is H, D, halogen, -CN, -OH, -SH, -N(R15 )2 , -NR15 S(=O)2 (C1 -C4 Alkyl), -S(C1 -C4 Alkyl), -S(=O)(C1 -C4 Alkyl), -S(=O)2 (C1 -C4 Alkyl), -S(=O)2 N(R15 )2 , -OC(=O)(C1 -C4 Alkyl), -CO2 H, -CO2 (C1 -C4 Alkyl), -C(=O)N(R15 )2 , -NR15 C(=O)(C1 -C4 Alkyl), -NR15 C(=O)O(C1 -C4 Alkyl), -OC(=O)N(R15 )2 , -NR15 C(=O)N(R15 )2 、C1 -C4 Alkyl, C2 -C4 Alkenyl, C2 -C4 Alkynyl, C1 -C4 Alkoxy, C1 -C4 deuterated alkyl, C1 -C4 deuterated alkoxy, C1 -C4 Fluoroalkyl, C1 -C4 Fluoroalkoxy, C1 -C4 Heteroalkyl or substituted or unsubstituted monocyclic C2 -C5 Heterocycloalkyl; X2 for CR2 or N; R2 is H, D, halogen, -CN, -OH, -SH, -N(R15 )2 , -NR15 S(=O)2 (C1 -C4 Alkyl), -S(C1 -C4 Alkyl), -S(=O)(C1 -C4 Alkyl), -S(=O)2 (C1 -C4 Alkyl), -S(=O)2 N(R15 )2 , -OC(=O)(C1 -C4 Alkyl), -CO2 H, -CO2 (C1 -C4 Alkyl), -C(=O)N(R15 )2 , -NR15 C(=O)(C1 -C4 Alkyl), -NR15 C(=O)O(C1 -C4 Alkyl), -OC(=O)N(R15 )2 , -NR15 C(=O)N(R15 )2 、C1 -C4 Alkyl, C2 -C4 Alkenyl, C2 -C4 Alkynyl, C1 -C4 Alkoxy, C1 -C4 deuterated alkyl, C1 -C4 deuterated alkoxy, C1 -C4 Fluoroalkyl, C1 -C4 Fluoroalkoxy or C1 -C4 Heteroalkyl or substituted or unsubstituted monocyclic C2 -C5 Heterocycloalkyl; or R1 and R2 Together with the intervening atom, a substituted or unsubstituted 5-membered fused ring or a substituted or unsubstituted 6-membered fused ring has 0 to 3 N atoms and 0 to 2 O or S atoms in the ring; x3 for CR3 or N; R3 is H, D, halogen, -CN, -OH, -SH, -N(R15 )2 , -NR15 S(=O)2 (C1 -C4 Alkyl), -S(C1 -C4 Alkyl), -S(=O)(C1 -C4 Alkyl), -S(=O)2 (C1 -C4 Alkyl), -S(=O)2 N(R15 )2 , -OC(=O)(C1 -C4 Alkyl), -CO2 H, -CO2 (C1 -C4 Alkyl), -C(=O)N(R15 )2 , -NR15 C(=O)(C1 -C4 Alkyl), C1 -C4 Alkyl, C2 -C4 Alkenyl, C2 -C4 Alkynyl, C1 -C4 Alkoxy, C1 -C4 deuterated alkyl, C1 -C4 deuterated alkoxy, C1 -C4 Fluoroalkyl, C1 -C4 Fluoroalkoxy, C1 -C4 Heteroalkyl or substituted or unsubstituted monocyclic C2 -C5 Heterocycloalkyl; each X4 independently CH or N; R4 is H, D, F or -CH3 ;R5 is H, D, F or -CH3 ; or R4 and R5 together form a bridging bond which is -CH2 -or-CH2 CH2 -; each R6 independently H, D, F, -OH or -CH3 ; m is 0, 1 or 2; R7 is H, D, halogen, -CN, -OH, C1 -C4 Alkyl, C2 -C4 Alkenyl, C2 -C4 Alkynyl, C1 -C4 Alkoxy, C1 -C4 deuterated alkyl, C1 -C4 deuterated alkoxy, C1 -C4 Fluoroalkyl, C1 -C4 Fluoroalkoxy or C1 -C4 Heteroalkyl; L does not exist, is -Y2 -L1 -, -L1 -Y2 -, cyclopropyl, cyclobutyl or bicyclo[1.1.1]pentyl; Y2 Does not exist, is -O-, -S-, -S(=O)-, -S(=O)2 -, -S(=O)2 NR15 -, -CH2 -, -CH=CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C (=O)NR15 -, -NR15 C(=O)-, -OC(=O)NR15 -, -NR15 C(=O)O-, -NR15 C(=O)NR15 -, -NR15 S(=O)2 -or-NR15 -; L1 Absent or substituted or unsubstituted C1 -C4 Alkylene; X5 for NR8 or N; R8 for H, D, C1 -C6 Alkyl, C1 -C6 deuterated alkyl, C1 -C6 Fluoroalkyl, C1 -C6 Heteroalkyl, -C(=O)(C1 -C4 Alkyl), -CO2 (C1 -C4 Alkyl), -C(=O)N(R15 )2 , -S(=O)2 (C1 -C4 Alkyl), -S(=O)2 N(R15 )2 , substituted or unsubstituted C3 -C6 Cycloalkyl or substituted or unsubstituted monocyclic C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; R9 is H, D, F or -CH3 ; Y is -CR10 R11 -, -O-, -S-, -S(=O)-, -S(=O)2- or -NR17 -;R10 is H, D, halogen, -CN, -OH, C1 -C6 Alkyl, C2 -C4 Alkenyl, C2 -C4 Alkynyl, C1 -C6 Alkoxy, C1 -C6 Fluoroalkyl, -SR12 , -S(=O)R14 , -S(=O)2 R14 , or -N(R12 )2 ;R11 is H, D, F or -CH3 ; or R9 and R11 together form a bridging bond which is -CH2 -or-CH2 CH2 -; each R12 independently H, C1 -C4 Alkyl, C1 -C4 deuterated alkyl, C1 -C4 Fluoroalkyl, C1 -C4 Heteroalkyl, substituted or unsubstituted C3 -C6 Cycloalkyl, substituted or unsubstituted C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl; R14 for C1 -C4 Alkyl, C1 -C4 deuterated alkyl, C1 -C4 Fluoroalkyl, C1 -C4 Heteroalkyl, substituted or unsubstituted C3 -C6 Cycloalkyl, substituted or unsubstituted C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl; R15 is H or substituted or unsubstituted C1 -C6 Alkyl; each R16 independently H, D, halogen, -CN, -OH, -N(R15 )2 , -NR15 S(=O)2 (C1 -C4 Alkyl), -S(C1 -C4 Alkyl), -S(=O)(C1 -C4 Alkyl), -S(=O)2 (C1 -C4 Alkyl), -C(=O)(C1 -C4 Alkyl), -OC(=O)(C1 -C4 Alkyl), -CO2 H, -CO2 (C1 -C4 Alkyl), -NR15 C(=O)(C1 -C4 Alkyl), -C(=O)N(R15 )2 , -NR15 C(=O)O(C1 -C4 Alkyl), -OC(=O)N(R15 )2 、C1 -C4 Alkyl, C2 -C4 Alkenyl, C2 -C4 Alkynyl, C1 -C4 Alkoxy, C1 -C4 deuterated alkyl, C1 -C4 deuterated alkoxy, C1 -C4 Fluoroalkyl, C1 -C4 Fluoroalkoxy, C1 -C4 Heteroalkyl, substituted or unsubstituted C3 -C6 Cycloalkyl, substituted or unsubstituted monocyclic C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; n is 0, 1 or 2; R17 for-L5 -R14 ; and L5 Does not exist, is -S(=O)2 -, -C(=O)-, -CO2 -or-C(=O)N(R15 )-. In another aspect, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image007
Formula (I) where, X1 for CH or N; R1 is H, D, halogen, -CN, -OH, -N(R15 )2 , -NR15 S(=O)2 (C1 -C4 Alkyl), -OC(=O)(C1 -C4 Alkyl), -CO2 H, -CO2 (C1 -C4 Alkyl), -NR15 C(=O)(C1 -C4 Alkyl), -NR15 C(=O)O(C1 -C4 Alkyl), -OC(=O)N(R15 )2 , -NR15 C(=O)N(R15 )2 、C1 -C4 Alkyl, C2 -C4 Alkenyl, C2 -C4 Alkynyl, C1 -C4 Alkoxy, C1 -C4 deuterated alkyl, C1 -C4 deuterated alkoxy, C1 -C4 Fluoroalkyl, C1 -C4 Fluoroalkoxy, C1 -C4 Heteroalkyl or substituted or unsubstituted monocyclic C2 -C5 Heterocycloalkyl; X2 for CR2 or N; R2 is H, D, halogen, -CN, -OH, -N(R15 )2 , -NR15 S(=O)2 (C1 -C4 Alkyl), -OC(=O)(C1 -C4 Alkyl), -CO2 H, -CO2 (C1 -C4 Alkyl), -NR15 C(=O)(C1 -C4 Alkyl), -NR15 C(=O)O(C1 -C4 Alkyl), -OC(=O)N(R15 )2 , -NR15 C(=O)N(R15 )2 、C1 -C4 Alkyl, C2 -C4 Alkenyl, C2 -C4 Alkynyl, C1 -C4 Alkoxy, C1 -C4 deuterated alkyl, C1 -C4 deuterated alkoxy, C1 -C4 Fluoroalkyl, C1 -C4 Fluoroalkoxy or C1 -C4 Heteroalkyl; or R1 and R2 together with intervening atoms form a substituted or unsubstituted 5-membered fused ring having 0 to 3 N atoms and 0 to 2 O or S atoms in the ring; X3 for CR3 or N; R3 is H, D, halogen, -CN, -OH, -N(R15 )2 , -NR15 S(=O)2 (C1 -C4 Alkyl), -OC(=O)(C1 -C4 Alkyl), -CO2 H, -CO2 (C1 -C4 Alkyl), -NR15 C(=O)(C1 -C4 Alkyl), C1 -C4 Alkyl, C2 -C4 Alkenyl, C2 -C4 Alkynyl, C1 -C4 Alkoxy, C1 -C4 deuterated alkyl, C1 -C4 deuterated alkoxy, C1 -C4 Fluoroalkyl, C1 -C4 Fluoroalkoxy or C1 -C4 Heteroalkyl; Each X4 independently CH or N; R4 is H, D, F or -CH3 ;R5 is H, D, F or -CH3 ; or R4 and R5 together form a bridging bond which is -CH2 -or-CH2 CH2 -; each R6 independently H, D, F, -OH or -CH3 ; m is 0, 1 or 2; R7 is H, D, halogen, -CN, -OH, C1 -C4 Alkyl, C1 -C4 Alkoxy, C1 -C4 deuterated alkyl, C1 -C4 deuterated alkoxy, C1 -C4 Fluoroalkyl, C1 -C4 Fluoroalkoxy or C1 -C4 Heteroalkyl; L does not exist, is -Y2 -L1 -, -L1 -Y2 -, cyclopropyl, cyclobutyl or bicyclo[1.1.1]pentyl; Y2 Does not exist, is -O-, -S-, -S(=O)-, -S(=O)2 -, -S(=O)2 NR15 -, -CH2 -, -CH=CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C (=O)NR15 -, -NR15 C(=O)-, -OC(=O)NR15 -, -NR15 C(=O)O-, -NR15 C(=O)NR15 -, -NR15 S(=O)2 -or-NR15 -; L1 Absent or substituted or unsubstituted C1 -C4 Alkylene; X5 for NR8 or N; R8 for H, D, C1 -C6 Alkyl, C1 -C6 deuterated alkyl, C1 -C6 Fluoroalkyl, C1 -C6 Heteroalkyl, -C(=O)(C1 -C4 Alkyl), -CO2 (C1 -C4 Alkyl), -C(=O)N(R15 )2 , -S(=O)2 (C1 -C4 Alkyl), -S(=O)2 N(R15 )2 , substituted or unsubstituted C3 -C6 Cycloalkyl or substituted or unsubstituted monocyclic C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; R9 is H, D or -CH3 ; Y is -CR10 R11 -, -O-, -S-, -S(=O)-, -S(=O)2- or -NR17 -;R10 is H, D, halogen, -CN, -OH, C1 -C6 Alkyl, C1 -C6 Alkoxy, C1 -C6 Fluoroalkyl, -SR12 , -S(=O)R14 , -S(=O)2 R14 , or -N(R12 )2 ;R11 is H, D or -CH3 ; or R9 and R11 together form a bridging bond which is -CH2 -or-CH2 CH2 -; each R12 independently H, C1 -C4 Alkyl, C1 -C4 deuterated alkyl, C1 -C4 Fluoroalkyl, C1 -C4 Heteroalkyl, substituted or unsubstituted C3 -C6 Cycloalkyl, substituted or unsubstituted C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl; R14 for C1 -C4 Alkyl, C1 -C4 deuterated alkyl, C1 -C4 Fluoroalkyl, C1 -C4 Heteroalkyl, substituted or unsubstituted C3 -C6 Cycloalkyl, substituted or unsubstituted C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl; R15 is H or substituted or unsubstituted C1 -C6 Alkyl; each R16 independently H, D, halogen, -CN, -OH, -N(R15 )2 , -NR15 S(=O)2 (C1 -C4 Alkyl), -S(C1 -C4 Alkyl), -S(=O)2 (C1 -C4 Alkyl), -C(=O)(C1 -C4 Alkyl), -OC(=O)(C1 -C4 Alkyl), -CO2 H, -CO2 (C1 -C4 Alkyl), -NR15 C(=O)(C1 -C4 Alkyl), -C(=O)N(R15 )2 , -NR15 C(=O)O(C1 -C4 Alkyl), -OC(=O)N(R15 )2 、C1 -C4 Alkyl, C2 -C4 Alkenyl, C2 -C4 Alkynyl, C1 -C4 Alkoxy, C1 -C4 deuterated alkyl, C1 -C4 deuterated alkoxy, C1 -C4 Fluoroalkyl, C1 -C4 Fluoroalkoxy, C1 -C4 Heteroalkyl, substituted or unsubstituted C3 -C6 Cycloalkyl, substituted or unsubstituted monocyclic C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; n is 0, 1 or 2; R17 for-L5 -R14 ; and L5 Does not exist, is -S(=O)2 -, -C(=O)-, -CO2 -or-C(=O)N(R15 )-. For any and all embodiments, substituents are selected from a subset of the listed alternatives. For example, in some embodiments, Y is -CR10 R11 -, -O-, -S-, -S(=O)-, -S(=O)2- or -NR17 -. In other embodiments, Y is -CR10 R11 -, -O-, or -NR17 -. In some embodiments, Y is -CR10 R11 -. In some embodiments, m is 0, 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, L is absent, -O-, -S-, -CH2 -, -CH2 CH2 -, -CH2 O-, -OCH2 -, -CH2 NR15 -, -NR15 CH2 -, -CH=CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C (=O)NR15 -, -NR15 C(=O)-, -OC(=O)NR15 -, -NR15 C(=O)O-, -NR15 C(=O)NR15 -, -NR15 S(=O)2 -, -NR15 -, cyclopropyl, cyclobutyl or bicyclo[1.1.1]pentyl. In some embodiments, L is absent, -O-, -S-, -CH2 -, -CH2 CH2 -, -CH2 O-, -OCH2 -, -CH2 NR15 -, -NR15 CH2 -, -CH=CH-, -C≡C-, -C(=O)NR15 -, -NR15 C(=O)-, -OC(=O)NR15 -, -NR15 C(=O)O-, -NR15 C(=O)NR15 -, -NR15 S(=O)2 -, -NR15 -, cyclopropyl, cyclobutyl or bicyclo[1.1.1]pentyl. In some embodiments, L is absent or -C≡C-. In some embodiments, R9 for H; R11 is H; or R9 and R11 together form a bridging bond which is -CH2 CH2 -. In some embodiments, R9 is H; and R11 for H. In some embodiments, the compound has the structure of formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image009
Formula (II). In some embodiments, L is absent. In some embodiments, the compound has the structure of formula (III), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image011
Formula (III). In some embodiments, R4 for H; R5 is H; or R4 and R5 together form a bridging bond which is -CH2 CH2 -. In some embodiments, R4 for H; R5 for H. In some embodiments, R4 and R5 together form a bridging bond which is -CH2 CH2 -. In some embodiments, the compound has the structure of formula (IV), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image013
Formula (IV) In some embodiments, the compound has the structure of formula (V), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image015
Formula (V) In some embodiments, the compound has the structure of formula (VI), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image017
Formula (VI) In some embodiments, R4 for H; R5 is H; or R4 and R5 together form a bridging bond which is -CH2 CH2 -. In some embodiments, the compound has the structure of formula (VII), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image019
Formula (VII) In some embodiments, the compound has the structure of formula (VIII), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image021
Formula (VIII). In some embodiments, R10 For H, D, F, -CN, -OH, C1 -C6 Alkyl, C1 -C6 Alkoxy, C1 -C6 Fluoroalkyl, or -N(R12 )2 . In some embodiments, R10 For H, D, F, -OH, C1 -C6 Alkyl, C1 -C6 Alkoxy, or -N(R12 )2 . In some embodiments, R10 is H, D, F, -CN, -OH, -CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 , -NH2 , -NH(CH3 ) or -N(CH3 )2 . In some embodiments, R10 is H, -OH, -CH3 、-OCH3 , -NH2 , -NH(CH3 ) or -N(CH3 )2 . In some embodiments, R10 is H, -OH or -NH2 . In some embodiments, R10 for -OH. In some embodiments, no more than two x2 、X3 、X4 、X4 for N. In some embodiments, if two X4 are N, then X2 for CR2 and X3 for CR3 ; or if an X4 is N and another X4 for CH, only X2 and X3 One of them is N. In some embodiments, containing X2 、X3 、X4 、X4 The 6-membered ring has not more than two N atoms in the ring. In some embodiments, X2 for CR2 ;X3 for CR3 or N; each X4 for CH; or for each X4 an N; or an X4 is N and another X4 for CH. In some embodiments, X2 for CR2 ;X3 for CR3 ; Each X4 for CH; or for each X4 an N; or an X4 is N and another X4 for CH. In some embodiments, X2 for CR2 ;X3 for CR3 ; Each X4 for CH. In some embodiments, R1 H, D, F, Cl, -CN, -OH, -SH, -NH2 , -NH(CH3 ), -N(CH3 )2 , -NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H, -CO2 CH3 , -NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-SCH3 、-SCH2 CH3 、-SCH(CH3 )2 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH, -CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 or -CH2 N(CH3 )2 ;2 For H, D, F, Cl, -CN, -OH, -SH, -NH2 , -NH(CH3 ), -N(CH3 )2 , -NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H, -CO2 CH3 , -NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-SCH3 、-SCH2 CH3 、-SCH(CH3 )2 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH, -CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 or -CH2 N(CH3 )2 ; or R1 and R2 together with an intervening atom form a substituted or unsubstituted 5-membered fused ring or a substituted or unsubstituted 6-membered fused ring having 0 to 3 N atoms and 0 to 2 O or S atoms in the ring, The ring is substituted or unsubstituted dihydrofuranyl, substituted or unsubstituted dihydropyrrolyl, substituted or unsubstituted dioxolyl, substituted or unsubstituted Furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted isoxazolyl or substituted or unsubstituted isothiazolyl, Substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazine or substituted or unsubstituted pyridazinyl; R3 For H, D, F, Cl, -CN, -OH, -SH, -NH2 , -NH(CH3 ), -N(CH3 )2 , -NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H, -CO2 CH3 , -NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-SCH3 、-SCH2 CH3 、-SCH(CH3 )2 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH, -CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 or -CH2 N(CH3 )2 . In some embodiments, R1 For H, D, F, Cl, -CN, -OH, -NH2 , -NH(CH3 ), -N(CH3 )2 , -NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H, -CO2 CH3 , -NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH, -CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 or -CH2 N(CH3 )2 ;2 For H, D, F, Cl, -CN, -OH, -NH2 , -NH(CH3 ), -N(CH3 )2 , -NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H, -CO2 CH3 , -NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH, -CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 or -CH2 N(CH3 )2 ; or R1 and R2 Together with the intervening atom, a substituted or unsubstituted 5-membered fused ring having 0 to 3 N atoms and 0 to 2 O or S atoms in the ring, the ring is a substituted or unsubstituted dihydro Furyl, substituted or unsubstituted dioxolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, Substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazole R, substituted or unsubstituted isoxazolyl or substituted or unsubstituted isothiazolyl; R3 For H, D, F, Cl, -CN, -OH, -NH2 , -NH(CH3 ), -N(CH3 )2 , -NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H, -CO2 CH3 , -NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH, -CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 or -CH2 N(CH3 )2 . In some embodiments, R1 For H, D, F, Cl, -CN, -OH, -SH, -NH2 , -NH(CH3 ), -N(CH3 )2 、-CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-SCH3 、-SCH2 CH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 or -OCH2 CF3 ;2 is H, D, F, Cl, -CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-SCH3 、-SCH2 CH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-OCH2 F, -OCHF2 、-OCF3 or -OCH2 CF3 ;3 is H, D, F, Cl, -CH3 、-OCH3 、-SCH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 or -OCF3 . In some embodiments, R1 For H, D, F, Cl, -CN, -OH, -NH2 , -NH(CH3 ), -N(CH3 )2 、-CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 or -OCH2 CF3 ;2 is H, D, F, Cl, -CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-OCH2 F, -OCHF2 、-OCF3 or -OCH2 CF3 ;3 is H, D, F, Cl, -CH3 、-OCH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 or -OCF3 . In some embodiments, R1 -OH, -SH, -NH2 , -NH(CH3 ), -N(CH3 )2 、-CH3 、-OCH3 、-SCH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-OCH2 F, -OCHF2 、-OCF3 or -OCH2 CF3 ;2 is H, D, F, Cl, -CH3 、-CD3 、-CH2 F, -CHF2 or -CF3 ;3 for H. In some embodiments, R1 -OH, -NH2 , -NH(CH3 ), -N(CH3 )2 、-CH3 、-OCH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-OCH2 F, -OCHF2 、-OCF3 or -OCH2 CF3 ;2 is H, D, F, Cl, -CH3 、-CD3 、-CH2 F, -CHF2 or -CF3 ;3 for H. In some embodiments, R1 For H, D, F, Cl, -CN, -OH, -NH2 , -NH(CH3 ), -N(CH3 )2 、-CH3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 or -OCF3 ;2 For H, D, F, Cl, -CN, -OH, -CH3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 or -OCF3 . In some embodiments, R1 -OH, -NH2 , -NH(CH3 ), -N(CH3 )2 、-OCH3 , -OCD3 、-OCH2 F, -OCHF2 or -OCF3 ;2 For F, Cl, -CN, -OH, -CH3 、-OCH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 or -OCF3 . In some embodiments, R1 -OH or -OCH3 ;2 is H, D, F, Cl, -CH3 or -CF3 . In some embodiments,
Figure 02_image023
for
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
,
Figure 02_image031
,
Figure 02_image033
or
Figure 02_image035
. In some embodiments,
Figure 02_image037
for
Figure 02_image039
,
Figure 02_image041
or
Figure 02_image043
. In some embodiments,
Figure 02_image045
for
Figure 02_image047
. In some embodiments,
Figure 02_image049
for
Figure 02_image051
or
Figure 02_image053
. In some embodiments,
Figure 02_image055
for
Figure 02_image057
. In some embodiments,
Figure 02_image059
for
Figure 02_image061
. In some embodiments,
Figure 02_image063
for
Figure 02_image065
,
Figure 02_image067
or
Figure 02_image069
. In some embodiments, X2 for N; X3 for N; for each X4 for CH. In some embodiments,
Figure 02_image071
for
Figure 02_image073
. In some embodiments, the compound has the structure of formula (IX), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image075
Formula (IX). In some embodiments, R1 H, D, F, Cl, -CN, -OH, -SH, -NH2 , -NH(CH3 ), -N(CH3 )2 , -NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H, -CO2 CH3 , -NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-SCH3 、-SCH2 CH3 、-SCH(CH3 )2 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH, -CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 or -CH2 N(CH3 )2 . In some embodiments, R1 For H, D, F, Cl, -CN, -OH, -NH2 , -NH(CH3 ), -N(CH3 )2 , -NHS(=O)2 CH3 、-OC(=O)CH3 、-CO2 H, -CO2 CH3 , -NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH, -CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 or -CH2 N(CH3 )2 . In some embodiments, R1 For H, D, F, Cl, -CN, -OH, -SH, -NH2 , -NH(CH3 ), -N(CH3 )2 、-CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-SCH3 、-SCH2 CH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 or -OCH2 CF3 . In some embodiments, R1 For H, D, F, Cl, -CN, -OH, -NH2 , -NH(CH3 ), -N(CH3 )2 、-CH3 、-CH2 CH3 、-OCH3 、-OCH2 CH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 or -OCH2 CF3 . In some embodiments, R1 -OH, -SH, -NH2 , -NH(CH3 ), -N(CH3 )2 、-CH3 、-OCH3 、-SCH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-OCH2 F, -OCHF2 、-OCF3 or -OCH2 CF3 . In some embodiments, R1 -OH, -NH2 , -NH(CH3 ), -N(CH3 )2 、-CH3 、-OCH3 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-OCH2 F, -OCHF2 、-OCF3 or -OCH2 CF3 . In some embodiments, R8 for H, D, -CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH(CH3 )CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-CD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 , -CHFCH3 、-CH2 CH2 F, -CH2 CH2 OH, -CH2 CH2 OCH3 、-CH2 CH2 NH2 、-CH2 CH2 NHCH3 、-CH2 CH2 N(CH3 )2 , -C(=O)CH3 , -C(=O)CH2 CH3 、-C(=O)CH(CH3 )2 、-CO2 CH3 、-CO2 CH2 CH3 、-CO2 CH(CH3 )2 , -C(=O)NHCH3 , -S(=O)2 CH3 , -S(=O)2 NHCH3 , substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl or substituted or unsubstituted tetrahydrothiopyranyl. In some embodiments, R8 for -CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH(CH3 )CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-CD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 , -CHFCH3 、-CH2 CH2 F, -CH2 CH2 OH, -CH2 CH2 OCH3 、-CH2 CH2 NH2 、-CH2 CH2 NHCH3 、-CH2 CH2 N(CH3 )2 , substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl or substituted or unsubstituted tetrahydropyranyl. In some embodiments, R8 H, -CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH(CH3 )CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-CD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 , -CHFCH3 、-CH2 CH2 F, -CH2 CH2 OH, -CH2 CH2 OCH3 、-CH2 CH2 NH2 、-CH2 CH2 NHCH3 、-CH2 CH2 N(CH3 )2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl. In some embodiments, R8 H, -CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-CD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl. In some embodiments, R8 for -CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 or cyclopropyl. In some embodiments, R8 for -CH(CH3 )2 or cyclopropyl. In some embodiments, each R12 independently H, C1 -C4 Alkyl, C1 -C4 deuterated alkyl, C1 -C4 Fluoroalkyl, C1 -C4 Heteroalkyl, substituted or unsubstituted C3 -C6 Cycloalkyl, substituted or unsubstituted C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R12 independently H, C1 -C4 Alkyl, C1 -C4 Heteroalkyl, substituted or unsubstituted C3 -C6 Cycloalkyl, substituted or unsubstituted C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R12 independently H, C1 -C4 Alkyl, C1 -C4 Heteroalkyl, substituted or unsubstituted C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R12 independently H, C1 -C4 Alkyl, or substituted or unsubstituted C2 -C6 Heterocycloalkyl. In some embodiments, each R12 independently H or C1 -C4 alkyl. In some embodiments, when two R12 attached to the N atom, then an R12 for H or C1 -C4 alkyl. In some embodiments, when two R12 attached to the N atom, then an R12 for H or C1 -C4 alkyl, and another R12 for H, C1 -C4 Alkyl, C1 -C4 Heteroalkyl, substituted or unsubstituted C3 -C6 Cycloalkyl, substituted or unsubstituted C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl. In some embodiments, when two R12 attached to the N atom, then an R12 for H or C1 -C4 alkyl, and another R12 for H, C1 -C4 Alkyl, C1 -C4 Heteroalkyl, substituted or unsubstituted C2 -C6 Heterocycloalkyl or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, when two R12 attached to the N atom, then an R12 for H or C1 -C4 alkyl, and another R12 for H, C1 -C4 Alkyl, C1 -C4 deuterated alkyl, C1 -C4 Fluoroalkyl, C1 -C4 Heteroalkyl, substituted or unsubstituted C3 -C6 Cycloalkyl, substituted or unsubstituted C2 -C6 Heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R16 independently H, D, F, Cl, -CN, -OH, -NH2 , -NH(CH3 ), -N(CH3 )2 , -NHS(=O)2 CH3 , -S(=O)2 CH3 , -C(=O)CH3 、-OC(=O)CH3 、-CO2 H, -CO2 CH3 , -NHC(=O)CH3 、-CH3 、-CH2 CH3 、-CH2 CH2 CH3 、-CH(CH3 )2 、-CH2 CH2 CH2 CH3 、-CH2 CH(CH3 )2 、-C(CH3 )3 、-CH=CH2 、-CH=CHCH3 , -C≡CH, -C≡CCH3 、-C≡CCH2 CH3 、-OCH3 、-OCH2 CH3 、-OCH(CH3 )2 、-CD3 , -OCD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 、-OCH2 F, -OCHF2 、-OCF3 、-OCH2 CF3 、-CH2 OH, -CH2 CH2 OH, -CH2 OCH3 、-CH2 OCH2 CH3 、-CH2 NH2 、-CH2 NHCH3 or -CH2 N(CH3 )2 , substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted Aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted tetrahydrofuran substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrothiopyranyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiopyranyl Morpholinyl or substituted or unsubstituted piperazinyl. In some embodiments, each R16 independently H, D, F, Cl, -CH3 、-CH2 CH3 、-CH(CH3 )2 、-C(CH3 )3 、-CD3 、-CH2 F, -CHF2 、-CF3 、-CH2 CF3 , substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl. In some embodiments, each R16 independently H, D, F, Cl, -CH3 、-CH2 CH3 、-CD3 、-CH2 F, -CHF2 、-CF3 or -CH2 CF3 . In some embodiments, the compound has the structure of formula (X), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image077
Formula (X). In some embodiments, the compound has the structure of formula (XI), or a pharmaceutically acceptable salt or solvate thereof:
Figure 02_image079
Formula (XI). Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be selected by one skilled in the art to result in stable moieties and compounds. In some embodiments, compounds described herein include, but are not limited to, those described in Table 1. Table 1.
Figure AA1
Figure AA2
Figure AA3
Figure AA4
Figure AA5
Figure AA7
Figure AA8
Figure AA9
 In some embodiments, provided herein is a pharmaceutically acceptable salt or solvate of a compound described in Table 1. In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts. Active metabolites of these compounds having the same type of activity are also included within the scope of the present invention. Furthermore, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. As used herein, "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., administering the substance to a subject does not cause undesirable biological effects. effects or will not interact in a deleterious manner with any component of the composition in which it is contained. The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting of the cationic form of the therapeutically active agent and a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent and a suitable cation. Forms of therapeutically active agents. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, eds.,Handbook of Pharmaceutical Salts: Properties, Selection and Use , Weinheim/Zürich: Wiley-VCH/VHCA, 2002. Pharmaceutical salts are generally more soluble and dissolve faster in gastric and intestinal juices than non-ionic species and are therefore suitable for solid dosage forms. Furthermore, since its solubility is generally a function of pH, selective dissolution in one part of the digestive tract or another is possible, and this ability can be manipulated with an aspect of delayed and sustained release properties. Furthermore, since the salt-forming molecules can be equilibrated in neutral form, transport across biomembranes can be tuned. In some embodiments, a "pharmaceutically acceptable acid addition salt" is provided by reacting a compound described herein with an acid to obtain a pharmaceutically acceptable salt. In some embodiments, the compounds described herein (ie, the free base form) are basic and react with organic or inorganic acids. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; -aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (caprylic acid); caproic acid (caprylic acid); caprylic acid (caprylic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; lauryl sulfate; acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptanoic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; Diacid; Glycerophosphoric Acid; Glycolic Acid; Hippuric Acid; Isobutyric Acid; Lactic Acid (DL); Lactobionic Acid; Lauric Acid; Maleic Acid; Malic Acid (-L); Malonic Acid; Mandelic Acid (DL); Methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; niacin; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p ); and undecylenic acid. In some embodiments, the compounds described herein are prepared as chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salts. In some embodiments, "pharmaceutically acceptable base addition salts" are provided by reacting a compound described herein with a base to obtain a pharmaceutically acceptable salt. In some embodiments, the compounds described herein are acidic and react with bases. In such cases, the acidic protons of the compounds described herein are replaced by metal ions, such as lithium, sodium, potassium, magnesium, calcium or aluminum ions. In some cases, compounds described herein are combined with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, Coordination with (hydroxymethyl) methylamine. In other instances, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases for forming salts with the compounds include acidic protons and include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide and its analogues. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts. It should be understood that references to pharmaceutically acceptable salts include solvent addition forms. In some embodiments, solvates contain stoichiometric or non-stoichiometric amounts of solvents and are formed during isolation or purification of compounds with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are preferably prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms. The methods and formulations described herein include the use of the compounds described hereinN - oxides (where appropriate), crystalline forms (also known as polymorphs) or pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity. In some embodiments, the sites on the organic radicals (eg, alkyl, aromatic rings) of the compounds described herein are susceptible to different metabolic reactions. Incorporation of suitable substituents on organic radicals will reduce, minimize or eliminate this metabolic pathway. In particular embodiments, suitable substituents that reduce or eliminate the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogen, deuterium, alkyl, haloalkyl, or deuterated alkyl. In another embodiment, the compounds described herein are isotopically labeled (eg, with radioactive isotopes) or labeled by other means including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Compounds described herein include isotopically labeled compounds that are identical to those described in the various formulas and structures presented herein, but in which one or more atoms differ by atomic mass or mass number from those found in nature. Common atomic mass or mass number atomic replacement. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as2 H.3 H.13 C.14 C.15 N.18 O.17 O.35 S,18 F.36 Cl. In one aspect, isotopically labeled compounds described herein (e.g., in combination with compounds such as3 H and14 Compounds of radioisotopes of C) are suitable for drug and/or substrate tissue distribution analysis. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen atoms of the compounds described herein are replaced with deuterium. In some embodiments, the compounds described herein possess one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. The compounds presented herein include all diastereomers, enantiomers, staster isomers and epimers and suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, ipsi, tra, E (entgegen (E), and Z (zusammen (Z)) isomers and suitable mixtures thereof. Individual stereoisomers are obtained as necessary by methods such as stereoselective synthesis and/or separation of stereoisomers by chiral chromatography columns. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form diastereoisomeric compound/salt pairs, separating the non- enantiomers and recover the optically pure enantiomer. In some embodiments, enantiomers are resolved using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereoisomers are separated by separation/resolution techniques based on differences in solubility. In other embodiments, stereoisomers are separated by chromatography or by formation of diastereoisomeric salts and separation by recrystallization or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis. In some embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted in vivo into the parent drug. Prodrugs are often useful because, in some cases, they are easier to administer than the parent drug. It is bioavailable, eg by oral administration, whereas the parent drug is not. Prodrugs can be substrates for transporters. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, prodrugs are designed to increase effective water solubility. Examples of prodrugs are, but are not limited to, the compounds described herein, which are administered as esters ("prodrugs"), but then undergo metabolic hydrolysis to yield the active entity. Another example of a prodrug is a short peptide (polyamino acid) bonded to an acid group, where the peptide undergoes metabolism to reveal the active moiety. In certain embodiments, following in vivo administration, the prodrug is chemically converted to a biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to a biologically, pharmaceutically or therapeutically active form of the compound. Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich base, Schiff base, amino acid conjugates, phosphates and sulfonates. See, for example, Design of Prodrugs, Bundgaard, A. eds., Elseview, 1985 and Method in Enzymology, Widder, K. et al. eds.; Academic, 1985, Vol. 42, pp. 309-396; Bundgaard, H. "Design and Application of Prodrugs” in A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1- 38 Each reference is incorporated herein by reference. In some embodiments, a prodrug is formed using a hydroxyl group in the compounds disclosed herein, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphoric acid Among esters, sugar esters, ethers and the like. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug, wherein the hydroxyl group is subsequently metabolized in vivo to yield a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (ie, a prodrug), which is then metabolized in vivo to yield a carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs. Prodrug forms of the compounds described herein are included within the scope of the claims, wherein the prodrugs are metabolized in vivo as described herein to produce the compounds described herein. In some instances, some of the compounds described herein are prodrugs of another derivative or active compound. Prodrug forms of the compounds described herein are included within the scope of the claims, wherein the prodrugs are metabolized in vivo as described herein to produce the compounds described herein. In some instances, some of the compounds described herein are prodrugs of another derivative or active compound. In some embodiments, prodrugs of the compounds disclosed herein permit targeted delivery of the compounds to specific regions of the gastrointestinal tract. Formation of pharmacologically active metabolites by colonic metabolism of drugs is a common "prodrug" approach for colon-specific drug delivery systems. In some embodiments, the prodrug is formed by forming a covalent bond between the drug and the carrier in such a way that after oral administration, the portion remains intact in the stomach and small intestine. This approach involves the formation of prodrugs, which are pharmacologically inactive derivatives of the parent drug molecule that require spontaneous or enzymatic transformation in a biological environment to release the active drug. Prodrugs are formed with improved delivery properties compared to the parent drug molecule. The stability problems of some drugs from the hostile environment of the upper gastrointestinal tract can be eliminated by the formation of prodrugs, which are converted to the parent drug molecule after reaching the colon. Site-specific drug delivery via site-specific prodrug activation can be achieved by exploiting some specific property at the target site, such as the altered pH of certain enzymes or achieve high activity. In some embodiments, the covalent linkage of the drug to the carrier forms a conjugate. Such conjugates include, but are not limited to, azo bond conjugates, glycoside conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates or amino acid conjugates . In additional or alternative embodiments, the compounds described herein, upon administration to an organism in need thereof, are metabolized to produce metabolites which are then used to produce a desired effect, including a desired therapeutic effect. A "metabolite" of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. As used herein, the term "metabolism" refers to the sum of processes, including but not limited to, hydrolytic reactions and enzyme-catalyzed reactions, by which a specific substance is altered by an organism. Thus, an enzyme can cause a specific structural change in a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronosyltransferase catalyzes the activation of glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups transfer. Metabolites of the compounds disclosed herein are optionally identified by administering the compound to a subject and analyzing a tissue sample from the subject, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. In some embodiments, the compounds described herein are rapidly metabolized after absorption from the gastrointestinal tract to metabolites that significantly reduce the activity of the FXR agonist. In additional or alternative embodiments, the compounds are rapidly metabolized in plasma. In additional or alternative embodiments, the compounds are rapidly metabolized by the gut. In additional or alternative embodiments, the compounds are rapidly metabolized by the liver.Compound Synthesis The compounds described herein are synthesized using standard synthetic techniques or using methods known in the art as well as those described herein. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology were employed. Compounds are prepared using standard organic chemistry techniques such as, for example, those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons Company. Alternative reaction conditions for the synthetic transformations described herein can be employed, such as solvent variations, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions. Starting materials were purchased from commercial sources or readily prepared. Suitable reference books and papers detailing the synthesis of reactants suitable for the preparation of the compounds described herein or refer to articles describing such preparations include, for example, "Synthetic Organic Chemistry", John Wiley & Sons Company, New York; S. R. Sandler et al. , "Organic Functional Group Preparations", 2nd ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd ed., W. A. Benjamin Co. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry ”, 2nd ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th ed., Wiley-Interscience, New York, 1992. Other suitable reference books and papers detailing the synthesis of reactants suitable for the preparation of the compounds described herein or refer to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials ", Second, Revised, and Supplemented Editions (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19 -509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions , Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (ed.) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3- 527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups” John Wiley & Sons, Vol. 73. The compounds described herein are prepared by the general synthetic pathways described in Schemes 1 to 11 below. In some embodiments, intermediates for the preparation of compounds described herein are prepared as outlined in Scheme 1.process 1
Figure 02_image213
In Scheme 1, the substituent X2 、X3 、X4 , R1 and R2 Department as described in this article. In some embodiments, X2 for C-R2 , X3 For C-H and each X4 for C-H. In some embodiments, X is a halide. In some embodiments, X is chlorine, bromine or iodine. In some embodiments,
Figure 107108918-A0304-12-0030-1
EsterI - 2 with halidesI - 1 Reaction under suitable metal-catalyzed cross-coupling reaction conditions givesI - 3 . In some embodiments, suitable metal-catalyzed cross-coupling conditions include the use of palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl2 or Pd(PPh3 )4 and a suitable base and a suitable solvent or solvent mixture for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base, such as Na2 CO3 or Cs2 CO3 . In some embodiments, suitable solvents or solvent mixtures are dioxane, acetonitrile, DME/EtOH, or ethanol. In some embodiments, a suitable time and a suitable temperature are from about 2 hours to about 18 hours (overnight) at about 50°C or about 100°C. In some embodiments, makeI - 3 After undergoing suitable hydrogenation conditions, followed by treatment under suitable acidic conditions, cyclohexanone is obtainedI - 4 . In some embodiments, suitable hydrogenation conditions include the use of palladium. Palladium-catalyzed hydrogenation conditions include the use of 10% Pd/C and hydrogen (1 atm) at a suitable temperature in a suitable solvent such as EtOAc, ethanol, methanol, or a combination of such solvents for a suitable amount of time. In some embodiments, a suitable amount of time at about room temperature is about 4.5 hours to about 18 hours (overnight). In some embodiments, suitable acidic conditions include a solution of formic acid in water and toluene at a suitable temperature for a suitable amount of time. In some embodiments, a suitable amount of time at a suitable temperature is about 4 hours at about 120°C. In some embodiments, a suitable amount of time at a suitable temperature is about 18 hours (overnight) at reflux. In some embodiments, suitable acidic conditions include PPTS in acetone and aqueous solution at a suitable temperature for a suitable amount of time. In some embodiments, a suitable amount of time at a suitable temperature is about 10 hours at about 60°C. In some embodiments, suitable acidic conditions include 3 M HCl and THF at a suitable temperature for a suitable amount of time. In some embodiments, a suitable amount of time at a suitable temperature is from about 3 hours to about overnight at about 60°C. In some embodiments, makeI - 4 Reaction under suitable one-carbon homologation conditions givesI - 5 . In some embodiments, suitable one-carbon homologation conditions include the use of phosphonium reagents. In some embodiments, suitable one-carbon homologation conditions include pretreatment of (methoxymethyl)triphenylphosphonium [Ph3 P+ CH2 OCH3 Cl- ] for the appropriate amount of time, after which cyclohexanone is addedI - 4 . In some embodiments, a suitable base is NaHMDS. In some embodiments, a suitable base is KHMDS or LiHMDS. In some embodiments, a suitable solvent is THF. In some embodiments, adding cyclohexanoneI - 4 Previously, a suitable amount of time at a suitable temperature is from about 30 minutes to about 2 hours at about 0°C. In some embodiments, addingI - 4 Thereafter, the reaction is allowed to continue for about 30 minutes to about 3 hours at about 0°C. In some embodiments, the reaction is allowed to warm to about room temperature overnight. In some embodiments, the subsequentI - 5 Under suitable acidic conditions, cis-formaldehyde and trans-formaldehyde can be obtainedI - 6 . In some embodiments, suitable acidic conditions include formic acid in water/toluene at about 120°C to about 130°C for about 2 hours to about overnight. In some embodiments, suitable acidic conditions include HCl in THF at about 60°C for about 1 hour or about 6 hours. In some embodiments, the aldehyde is furtherI - 6 Under appropriate alkaline conditions, the main trans aldehyde is obtainedI - 6 . In some embodiments, suitable basic conditions include NaOH at a suitable temperature in a suitable solvent mixture, such as H2 O, EtOH and PhMe for the appropriate amount of time. In some embodiments, THF is used instead of PhMe. In some embodiments, a suitable amount of time at a suitable temperature is from about 5.5 hours to about overnight at about room temperature. In some embodiments, suitable basic conditions include NaOMe in a suitable solvent, such as MeOH, at a suitable temperature for a suitable amount of time. In some embodiments, a suitable amount of time at a suitable temperature is from about 4 hours to about 18 hours at about room temperature. In some embodiments, further purification via crystallization or chromatography affords pure trans-aldehydeI - 6 . In some embodiments, intermediates for the preparation of compounds described herein are prepared as outlined in Scheme 2.process 2
Figure 02_image215
In Scheme 2, the substituent X2 、X3 、X4 , R1 , R2 and m are as described herein. In some embodiments, X2 for C-R2 , X3 For C-H and each X4 for C-H. In some embodiments, R6 For the alkyl. In some embodiments, R6 For methyl. In some embodiments, X is halogen. In some embodiments, X is chlorine, bromine or iodine. In some embodiments, theII - 1 Cool to a suitable temperature, react with a suitable solvent at a suitable temperature and for a suitable time under suitable metal-halogen exchange conditions, and subsequently react with a suitable ketoneII - 2 The reaction is continued for a suitable time and at a suitable temperature to giveII - 3 . In some embodiments, suitable metal-halogen exchange conditions include organometallic reagents. In some embodiments, a suitable solvent is THF. In some embodiments, the organometallic reagent is an alkyllithium. In some embodiments, the alkyllithium is n-butyllithium. In some embodiments, theII - 1 Cool to about -78°C before adding the organometallic reagent. In some embodiments, theII - 1 The reaction lasts about two hours, after which time the appropriate ketone is addedII - 2 . In some embodiments, after adding ketoneII - 2 Afterwards, the reaction of the intermediate organometallic reagent was continued for about 3 hours. In some embodiments, after adding ketoneII - 2 Afterwards, the intermediate organometallic reagent is reacted at about -78°C. In some embodiments, the alcoholII - 3 Reaction with a suitable solvent under suitable reducing conditions and at a suitable temperature for a suitable time forms a mixture of the dehydrated product and the reduced product. In some embodiments, the conditions include the use of trifluoroacetic acid and hydrosilane. In some embodiments, the hydrosilane is triethylsilane. In some embodiments, a suitable solvent is dichloromethane. In some embodiments, the temperature is from about 0°C to about room temperature or at about 0°C. In some embodiments, a suitable time is about overnight or about 1 hour. In some embodiments, the mixture of the reduced product and the dehydrated product is reacted with a suitable solvent under suitable conditions and at a suitable temperature for a suitable time to form a ketone. In some embodiments, a suitable solvent is a mixture of formic acid, toluene and water. In some embodiments, a suitable temperature is about 130°C. In some embodiments, a suitable time is about overnight. In some embodiments, a suitable solvent is a mixture of formic acid, THF and water. In some embodiments, a suitable temperature is about 80°C. In some embodiments, a suitable time is about 18 hours. In some embodiments, the ketone containing the dehydration by-product is completely reduced with a suitable solvent under suitable reducing conditions and at a suitable temperature for a suitable time to formII - 4 . In some embodiments, suitable reducing conditions include the use of hydrogen as the reducing agent. In some embodiments, the hydrogen is at a pressure of about 15 psi or about 30 psi. In some embodiments, olefin reduction includes use of a palladium catalyst. In some embodiments, the palladium catalyst is 10% palladium on carbon. In some embodiments, the solvent is ethyl acetate and concentrated HCl. In some embodiments, the solvent is ethyl acetate. In some embodiments, the temperature is about room temperature. In some embodiments, a suitable time is from about 30 minutes to about 18 hours. In some embodiments, the electrophile R is used in a suitable solvent and at a suitable temperature6 XpreprocessingII - 4 . In some embodiments, the electrophile is an alkyl halide. In some embodiments, X is chlorine, bromine or iodine. In some embodiments, the electrophile is methyl iodide. In some embodiments, the temperature is about -78°C. In some embodiments, the mixture is further reacted with a base for a suitable time and at a suitable temperature to form an alkylated product. In some embodiments, the base is lithium diisopropylamide. In some embodiments, a suitable time is about 2 hours. In some embodiments, the temperature is about -78°C. In some embodiments, the mixture is further allowed to warm to about room temperature over a suitable amount of time. In some embodiments, a suitable amount of time is about overnight. In some embodiments, as described in Scheme 1, the ketoneII - 4 converted to aldehydeII - 7 . Or in some embodiments, makeII - 4 Reaction under suitable one-carbon homologation conditions givesII - 5 . In some embodiments, suitable one-carbon homologation conditions include the use of phosphonium reagents. In some embodiments, suitable one-carbon homologation conditions include pretreatment of methyltriphenylphosphonium bromide [Ph3 P+ CH3 Br- ] for the appropriate amount of time, after which cyclohexanone is addedII - 4 . In some embodiments, suitable bases are organic bases. In some embodiments, a suitable base is an alkoxide base. In some embodiments, a suitable base is potassium tert-butoxide. In some embodiments, a suitable solvent is toluene. In some embodiments, a suitable time before adding the ketone is about 30 minutes. In some embodiments, the reaction temperature prior to addition of the ketone is about 100°C. In some embodiments, the ketoneII - 4 Add in a suitable solvent for a suitable amount of time. In some embodiments, after addition of the ketone, the reaction temperature is about 50°C. In some embodiments, the ketone is added in toluene. In some embodiments, the ketone is further reacted at a suitable temperature for a suitable amount of time. In some embodiments, the ketone is further reacted at about 100°C. In some embodiments, the ketone is further reacted for about 2 hours. In some embodiments, the olefinII - 5 undergoes hydration conditions to formII - 6 . In some embodiments, the hydration conditions include treatment with a reducing agent followed by an oxidizing agent. In some embodiments, the reducing agent andII - 5 React in a suitable solvent for a suitable amount of time. In some embodiments, the reducing agent is borane. In some embodiments, the reducing agent is BH3 -SMe2 . In some embodiments, the reducing agent is combined withII - 5 React in THF. In some embodiments, the reaction temperature is about 0°C. In some embodiments, the reaction is allowed to proceed for about one hour prior to adding the reducing agent. In some embodiments, the reaction is further continued at about room temperature. In some embodiments, the reaction is further continued for about 3 hours. In some embodiments, the intermediate borane product is further oxidized with an oxidizing agent in a suitable solvent at a suitable temperature to form the alcoholII - 6 and last for an appropriate amount of time. In some embodiments, the oxidizing agent is 30% H2 o2 . In some embodiments, the oxidation reaction is performed in the presence of a base. In some embodiments, the base is NaOH. In some embodiments, the solvent is H2 O. In some embodiments, a suitable amount of time is about overnight. In some embodiments, a suitable temperature is about room temperature. In some embodiments, the alcoholII - 6 undergoes oxidizing agents to form aldehydesII - 7 . In some embodiments, the oxidizing agent is a Swern oxidant in a suitable solvent at a suitable temperature for a suitable amount of time. In some embodiments, the Sven oxidizer is formed with DMSO and acetyl chloride. In some embodiments, a suitable solvent is dichloromethane. In some embodiments, a suitable temperature for the formation of the Sven oxidizer is about -78°C. In some embodiments, a suitable time for Sven oxidant formation is 30 minutes. In some embodiments, makeII - 6 Reacts with Sven oxidant at about -78°C. In some embodiments, makeII - 6 The reaction with Sven Oxidizer lasts about one hour. In some embodiments, base is then added at a suitable temperature for a suitable amount of time. In some embodiments, the base is an amine base. In some embodiments, the amine base is triethylamine. In some embodiments, a suitable temperature is about -78°C. In some embodiments, a suitable reaction time after adding the base is about one hour. In some embodiments, the oxidation reaction produces cis and trans isomers as a mixture ofII - 7 . In some embodiments, theII - 7 The balance of the cis/trans mixture is mainly transII - 7 . In some embodiments, a suitable reagent is a base. In some embodiments, the base is an inorganic base. In some embodiments, the base is sodium hydroxide. In some embodiments, suitable solvents are mixtures such as H2 O, EtOH and PhMe. In some embodiments, a suitable time is about 3 hours. In some embodiments, a suitable temperature is about room temperature. In some embodiments, further purification via crystallization or chromatography affords pure trans-aldehydeII - 7 . In some embodiments, intermediates for the preparation of compounds described herein are prepared as outlined in Scheme 3.process 3
Figure 02_image217
In Scheme 3, the substituent X2 、X3 、X4 , R1 , R2 and m are as described herein. In some embodiments, X2 for C-R2 , X3 For C-H and each X4 for C-H. In some embodiments, R6 For the alkyl. In some embodiments, R6 For methyl. In some embodiments, the ketone is treated with a base in a suitable solvent at a suitable temperatureIII - 1 The enolate is formed with a suitable base for a suitable amount of time. In some embodiments, the base is an organic base. In some embodiments, the organic base is LiHMDS. In some embodiments, enolate formation occurs at about -78°C. In some embodiments, a suitable solvent is THF. In some embodiments, a suitable time is about one hour. In some embodiments, the ketone is dissolved in a suitable solvent at a suitable temperatureIII - 1 The enolate is reacted with a suitable electrophile for a suitable amount of time to form an enol etherIII - 2 . In some embodiments, the electrophile forms a sulfate ester. In some embodiments, the electrophile is PhNTf2 . In some embodiments, a suitable temperature is about -78°C and a suitable time is about 2 hours. In some embodiments, the reaction is further warmed to a suitable temperature over a suitable period of time. In some embodiments, a suitable temperature is about room temperature for about overnight. In some embodiments, make
Figure 107108918-A0304-12-0030-1
acidIII - 3 with enol triflateIII - 2 Reaction under suitable metal-catalyzed cross-coupling reaction conditions givesIII - 4 . In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl2 and a suitable base and a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base, such as Na2 CO3 . In some embodiments, a suitable solvent is a dioxane/water mixture. In some embodiments, a suitable time and suitable temperature are about 6 hours at about 30°C. In some embodiments, makeIII - 4 Under suitable conditions for olefin reduction followed by treatment under suitable acidic conditions to give cyclohexanoneIII - 5 . In some embodiments, suitable reducing conditions include palladium-catalyzed hydrogenation conditions. In some embodiments, palladium-catalyzed hydrogenation conditions include the use of 10% Pd/C and hydrogen (1 atm) in a suitable solvent, such as EtOAc, at a suitable temperature for a suitable amount of time. In some embodiments, a suitable amount of time at about room temperature is about overnight. In some embodiments, suitable acidic conditions include using a solution of formic acid in water and toluene at a suitable temperature for a suitable amount of time. In some embodiments, a suitable amount of time at a suitable temperature is about overnight at about 120°C. In some embodiments, as shown in Scheme 1 and Scheme 2, the ketoneIII - 5 converted to aldehydes, respectivelyI - 6 or aldehydeII - 7 . In some embodiments, the compounds described herein are prepared as outlined in Scheme 4.process 4
Figure 02_image219
In scheme 4, the substituent Y, X1 、X2 、X3 、X4 , R1 , R2 and R8 Department as described in this article. In some embodiments, X2 for C-R2 , X3 For C-H and each X4 for C-H. In some embodiments, X is a halide. In some embodiments, X is iodine or bromine. In some embodiments, trans aldehydeIV - 1 with suitable anilineIV - 2 React under conditions suitable for reductive amination. In some embodiments, suitable reductive amination conditions include the use of a suitable reducing agent and acetic acid in a suitable solvent, such as DCE or DCM, at a suitable temperature for a suitable amount of time. In some embodiments, using NaBH(OAc)3 as a reducing agent. In some embodiments, a suitable temperature is about room temperature. In some embodiments, a suitable amount of time is from about one hour to about 2.5 hours. In some embodiments, suitable reaction conditions include acetic acid in a suitable solvent, such as methanol, at a suitable temperature for a suitable amount of time, followed by addition of the reducing agent. In some embodiments, a suitable temperature and time is about room temperature for about 5 minutes to about 4 hours. In some embodiments, the reaction is then further subjected to a suitable reducing agent, such as NaBH3 CN is performed for a suitable time and at a suitable temperature. In some embodiments, a suitable amount of time at about room temperature is about overnight. In some embodiments, ammonium chloride is amideIV - 3 , to get the compoundIV - 4 . Suitable acylation conditions include, but are not limited to, the use of a suitable base, such as TEA or pyridine, in a suitable solvent, such as DCM or toluene, at a suitable temperature, such as about room temperature to about 80°C, for a suitable amount of time, such as for about 1 hours to about overnight. In some embodiments, pyridine is used both as base and solvent. Other suitable conditions include the addition of DMAP. In some embodiments, boron-halogen exchange conditions can be used to generateIV - 4 preparation
Figure 107108918-A0304-12-0030-1
EsterIV - 5 . Suitable boron-halogen exchange conditions include, but are not limited to, the use of suitable organometallic reagents and suitable boron reagents. In some embodiments, suitable organometallic reagents include palladium. In some embodiments, suitable boron reagents include bis(pinacoto)diboron. In some embodiments, suitable palladium-catalyzed boron-halogen exchange conditions include Pd(dppf)Cl2 and a suitable base in a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is an acetate base, such as KOAc. In some embodiments, a suitable solvent is toluene. In some embodiments, a suitable time and a suitable temperature are from about 4 hours to about overnight and from about 100°C to about 115°C. In some embodiments, make
Figure 107108918-A0304-12-0030-1
EsterIV - 5 Reaction with a heteroaryl halide under suitable metal-catalyzed cross-coupling reaction conditions givesIV - 6 . In some embodiments, the heteroaryl halide is a heteroaryl bromide. In some embodiments, the heteroaryl halide is a pyrazolyl halide. In some embodiments, suitable metal-catalyzed cross-coupling conditions include the use of palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl2 or Pd(PPh3 )4 and a suitable base and a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base, such as K2 CO3 、Na2 CO3 or Cs2 CO3 . In some embodiments, a suitable solvent is dioxane or DMF. In some embodiments, water is a co-solvent. In some embodiments, a suitable time and a suitable temperature are from about 10 minutes to about 4 hours at about 50°C to about 80°C. In some embodiments, a suitable time and a suitable temperature are from about 0.5 hours to about 6 hours at about 80°C. In some embodiments, the aryl halideIV - 4 Reaction with a boron reagent under suitable metal-catalyzed cross-coupling reaction conditions givesIV - 6 . In some embodiments, the boron reagent is a heteroaryl
Figure 107108918-A0304-12-0030-1
acid. In some embodiments, the boron reagent is a heteroaryl
Figure 107108918-A0304-12-0030-1
esters. In some embodiments, the boron reagent is heteroaryl pinacyl
Figure 107108918-A0304-12-0030-1
esters. In some embodiments, the heteroarylboron reagent is a pyrazolylboron reagent. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl2 or Pd(PPh3 )4 and a suitable base and a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base, such as Cs2 CO3 、Na2 CO3 or K2 CO3 . In some embodiments, suitable solvents are dioxane/water or DMF/water mixtures. In some embodiments, a suitable time and a suitable temperature are from about 10 minutes to about 2 hours, at about 50°C to about 100°C, or at about 80°C. In some embodiments, Y contains a protected alcohol. In some embodiments, Y is protected with a silyl ether. In some embodiments, the protecting group is removed using suitable deprotection conditions, including suitable solvents, temperatures and times, to generate the free alcohol, yieldingIV - 6 . In some embodiments, suitable deprotection conditions include the use of aqueous HCl. In some embodiments, suitable solvents are water, THF, methanol, or a combination of solvents. In some embodiments, a suitable time at a suitable temperature is from about 30 minutes to about 1 hour at about 0°C to about room temperature. In some embodiments, the compounds described herein are prepared as outlined in Scheme 5.process 5
Figure 02_image221
In scheme 5, substituent Y, X1 、X2 、X3 、X4 , R1 , R2 , R4 , R5 , R6 , R8 and m are as described herein. In some embodiments, X2 for C-R2 , X3 For C-H and each X4 for C-H. In some embodiments, X is a halide. In some embodiments, X is iodine or bromine. In some embodiments, R is alkyl. In some embodiments, R is hydrogen. In some embodiments, the boron reagentV - 1 with heteroaryl halidesV - 2 Reaction under suitable metal-catalyzed cross-coupling reaction conditions givesV - 3 . In some embodiments, the heteroaryl halide is a heteroaryl bromide or heteroaryl iodide. In some embodiments, the heteroaryl halide is a pyrazolyl halide. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl2 and a suitable base and a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base, such as K2 CO3 . In some embodiments, a suitable solvent is a dioxane/water mixture. In some embodiments, a suitable time and suitable temperature are about 4 hours at about 80°C. In some embodiments, the aryl halideV - 4 with boron reagentV - 5 Reaction under suitable metal-catalyzed cross-coupling reaction conditions givesV - 3 . In some embodiments, the boron reagent is a heteroaryl
Figure 107108918-A0304-12-0030-1
acid. In some embodiments, the boron reagent is a heteroaryl
Figure 107108918-A0304-12-0030-1
esters. In some embodiments, the boron reagent is heteroaryl pinacyl
Figure 107108918-A0304-12-0030-1
esters. In some embodiments, the heteroarylboron reagent is a pyrazolylboron reagent. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl2 and a suitable base and a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base, such as K2 CO3 . In some embodiments, a suitable solvent is a dioxane/water mixture. In some embodiments, a suitable time and a suitable temperature are about 20 minutes at about 90°C. In some embodiments, the aldehyde and anilineV - 3 react under suitable reductive amination conditions to form aminesV - 9 . In some embodiments, suitable reductive amination conditions include the use of a suitable reducing agent in a suitable solvent, such as DCE or DCM, at a suitable temperature for a suitable amount of time. In some embodiments, acetic acid is added. In some embodiments, using NaBH(OAc)3 as a reducing agent. In some embodiments, a suitable temperature is about room temperature. In some embodiments, a suitable amount of time is from about one hour to about overnight. In some embodiments, suitable reaction conditions include acetic acid in a suitable solvent, such as methanol, at a suitable temperature for a suitable amount of time, followed by addition of the reducing agent. In some embodiments, a suitable temperature and time is about room temperature for about 5 minutes to about 4 hours. In some embodiments, the reaction is subjected to a suitable reducing agent, such as NaBH3 CN is performed for a suitable time and at a suitable temperature. In some embodiments, a suitable amount of time at about room temperature is about overnight. In some embodiments, aniline is chlorinated with acyl chlorideV - 9 , to get amideV - 10 . Suitable acylation conditions include, but are not limited to, the use of a suitable base, such as TEA or Pyridine is maintained for a suitable amount of time, such as for about 10 minutes to about overnight. Other suitable conditions include the addition of DMAP. In some embodiments, Y contains a protected alcohol. In some embodiments, Y is protected with a silyl ether. In some embodiments, the protecting group is removed using suitable deprotection conditions, including suitable solvents, temperatures and times, to generate the free alcohol, yieldingV - 10 . In some embodiments, suitable deprotection conditions include the use of aqueous HCl. In some embodiments, suitable solvents are water, THF, methanol, or a combination of solvents. In some embodiments, a suitable time at a suitable temperature is from about 30 minutes to about 1 hour at about 0°C to about room temperature. In some embodiments, the boron reagentV - 6 with heteroaryl halidesV - 7 Reaction under suitable metal-catalyzed cross-coupling reaction conditions givesV - 8 . In some embodiments, the heteroaryl halide is a heteroaryl bromide or heteroaryl iodide. In some embodiments, the heteroaryl halide is a pyrazolyl halide. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl2 and a suitable base and a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base, such as Na2 CO3 . In some embodiments, a suitable solvent is a mixture of dioxane, ethanol, and water. In some embodiments, a suitable time and suitable temperature is about overnight at about 80°C. In some embodiments, makeV - 8 After suitable nitro reduction conditions, aniline is obtainedV - 3 . Suitable nitro reducing conditions include palladium catalyzed hydrogenation conditions. In some embodiments, suitable palladium-catalyzed hydrogenation conditions include the use of 10% Pd/C and hydrogen (1 atm) in a suitable solvent, such as methanol, at a suitable temperature for a suitable amount of time. In some embodiments, suitable conditions include the addition of aqueous HCl. In some embodiments, a suitable amount of time at a suitable temperature is about one hour at about room temperature. In some embodiments, the compounds described herein are prepared as outlined in Scheme 6.process 6
Figure 02_image223
In Scheme 6, the substituent X1 、X2 、X3 、X4 , R1 , R2 , R4 , R5 , R6 , R8 , R12 and m are as described herein. In some embodiments, X2 for C-R2 , X3 For C-H and each X4 for C-H. In some embodiments, at a suitable temperature by using R12 X pairVI - 1 Ortho-alkylation, a suitable base and a suitable solvent such as THF to prepare the compoundVI - 2 Lasts for a suitable amount of time. In some embodiments, X is a halide. In some embodiments, a suitable base is NaH. In some embodiments, the compound is pretreated with a suitable base at a suitable temperature, such as at about 0°CVI - 1 for a suitable amount of time, such as about 0.5 hour, after which the halide R is added12 X. In some embodiments, a suitable time and temperature is about overnight at about 60°C. In some embodiments, the compounds described herein are prepared as outlined in Scheme 7.process 7
Figure 02_image225
In Scheme 7, the substituent X1 、X2 、X3 、X4 , R1 , R2 , R4 , R5 , R6 , R8 and m are as described herein. In some embodiments, X2 for C-R2 , X3 For C-H and each X4 for C-H. In some embodiments, makeVII - 1 Under suitable acidic conditions, the amineVII - 2 . In some embodiments, suitable acidic conditions include using TFA in a suitable solvent, such as DCM, at a suitable temperature for a suitable amount of time. In some embodiments, suitable acidic conditions include the use of HCl in a suitable solvent, such as dioxane, at a suitable temperature for a suitable amount of time. In some embodiments, a suitable temperature for a suitable amount of time is from about 0°C to about room temperature for about 0.5 hour to about 2 hours. In some embodiments, intermediates for the preparation of compounds described herein are prepared as outlined in Scheme 8.process 8
Figure 02_image227
In Scheme 8, the substituent X2 、X3 、X4 , R1 and R2 Department as described in this article. In some embodiments, X2 for C-R2 , X3 For C-H and each X4 for C-H. In some embodiments, X is a halide. In some embodiments, X is chlorine, bromine or iodine. In some embodiments, theVIII - 1 Cool to a suitable temperature, react with a suitable solvent at a suitable temperature and for a suitable time under suitable metal-halogen exchange conditions, and subsequently react with a suitable ketoneVIII - 2 The reaction is continued for a suitable time and at a suitable temperature to give the tertiary alcohol. In some embodiments, suitable metal-halogen exchange conditions include organometallic reagents. In some embodiments, a suitable solvent is THF. In some embodiments, the organometallic reagent is an alkyllithium. In some embodiments, the alkyllithium is n-butyllithium. In some embodiments, theVIII - 1 Cool to about -78°C before adding the organometallic reagent. In some embodiments, theVIII - 1 The reaction lasts about one hour after which time the appropriate ketone is addedVIII - 2 . In some embodiments, makeVIII - 1 The reaction lasted about 2 hours, after which the ketone was addedVIII - 2 . In some embodiments,VIII - 1 with ketonesVIII - 2 A suitable temperature for the reaction is about -78°C. In some embodiments, a tertiary alcohol is reacted under suitable allylation conditions for a suitable time in a suitable solvent and at a suitable temperature to formVIII - 3 , such conditions include the use of an allylation reagent and a Lewis acid. In some embodiments, a suitable allylation reagent is allyltrimethylsilane. In some embodiments, a suitable Lewis acid is BF3 -OEt2 . In some embodiments, a suitable solvent is DCM. In some embodiments, a suitable temperature for a suitable time is about -78°C for about 1 hour. In some embodiments, the reaction is further warmed to about room temperature for about overnight. In some embodiments, a suitable temperature for a suitable time is about 0°C for about overnight. In some embodiments, makeVIII - 3 Under suitable oxidative cracking conditions in a suitable solvent and at a suitable temperature for a suitable period of time to produceVIII - 4 . In some embodiments, oxidative cleavage conditions include the use of an osmium reagent and N-methylmorpholine N-oxide to form an intermediate diol. In some embodiments, the osmium reagent is OsO4 or K2 OSo4 -2H2 O. In some embodiments, a suitable solvent is an ACN/water mixture. In some embodiments, a suitable temperature for a suitable time is from about 0°C to about room temperature for about overnight. In some embodiments, the diol is cleaved under suitable oxidative cleavage conditions in a suitable solvent and at a suitable temperature for a suitable period of time to formVIII - 4 . In some embodiments, suitable oxidative cleavage conditions include using NaIO4 . In some embodiments, a suitable solvent is a THF/water mixture. In some embodiments, a suitable temperature for a suitable time is from about 0°C to about room temperature for about overnight. In some embodiments, makeVIII - 4 Reduction to primary alcohols under suitable reducing conditions and subsequent halogenation under suitable halogenation conditions to produceVIII - 5 . In some embodiments, suitable reducing conditions include the use of borohydride reagents. In some embodiments, reducing conditions include the use of NaBH in a suitable solvent at a suitable temperature4 for a suitable amount of time. In some embodiments, a suitable solvent is THF. In some embodiments, a suitable temperature for a suitable time is about 0°C for about one hour. In some embodiments, the reaction is warmed to about room temperature for about overnight. In some embodiments, alcohols are reacted under suitable halogenation conditions to produce alkyl halides. In some embodiments, suitable halogenation conditions are bromination conditions comprising the use of CBr in a suitable solvent at a suitable initial temperature4 , followed by PPh in a suitable solvent at a suitable temperature3 last for the right amount of time. In some embodiments, a suitable solvent is a halogenated solvent, such as DCM. In some embodiments, a suitable initial temperature is about 0°C. In some embodiments, adding PPh3 A suitable temperature and time thereafter is about 0°C for about one hour. In some embodiments, for adding PPh3 A suitable solvent is THF. In some embodiments, the reaction is further warmed to about room temperature for about overnight. In some embodiments, makeVIII - 5 undergoes intramolecular alkylation conditions to formVIII - 6 . In some embodiments, intramolecular alkylation conditions include a suitable base. In some embodiments, a suitable base is lithium diisopropylamide in a suitable solvent at a suitable temperature for a suitable amount of time. In some embodiments, a suitable solvent is a mixture of HMPA and THF. In some embodiments, a suitable temperature for a suitable amount of time is about -78°C for about 3 hours or about -78°C to room temperature for about overnight. In some embodiments, by adapting reducing conditions toVIII - 6 Reduction to alcohol followed by oxidation to aldehyde by suitable oxidation conditionsVIII - 7 . In some embodiments, suitable reducing conditions include using DIBALH in a suitable solvent at a suitable temperature for a suitable time. In some embodiments, a suitable solvent is DCM. In some embodiments, a suitable temperature for a suitable time is about -78°C for about one hour. In some embodiments, the reaction is further warmed to about room temperature for about two hours to produce the alcohol. In some embodiments, suitable oxidation conditions are chromium-based oxidations. In some embodiments, suitable oxidation conditions include using PCC in a suitable solvent at a suitable temperature for a suitable time. In some embodiments, silica gel is added. In some embodiments, a suitable solvent is DCM. In some embodiments, a suitable temperature is about room temperature for about 2 hours. Alternatively, in some embodiments, the oxidation conditions include the use of acetyl chloride and DMSO in a suitable solvent and an amine base at a suitable temperature for a suitable time. In some embodiments, a suitable amine base is TEA. In some embodiments, a suitable solvent is DCM. In some embodiments, a suitable temperature for a suitable amount of time is about -78°C for about one hour. In some embodiments, intermediates for the preparation of compounds described herein are prepared as outlined in Scheme 9.process 9
Figure 02_image229
In some embodiments, makeIX - 1 undergoes alcohol protection conditions to form the disilyl intermediate, followed by hydrolysis conditions to formIX - 2 . In some embodiments, alcohol protection conditions include the use of TBSCl and a suitable base in a suitable solvent at a suitable temperature and for a suitable period of time. In some embodiments, a suitable solvent is DMF. In some embodiments, a suitable base is imidazole. In some embodiments, a suitable temperature for a suitable time is about room temperature for about 2 hours. In some embodiments, the intermediate silyl ester is subjected to hydrolysis conditions to formIX - 2 . In some embodiments, the hydrolysis conditions include treatment with a base in a suitable solvent at a suitable temperature and for a suitable period of time. In some embodiments, suitable solvents are EtOH, H2 O, THF mixture. In some embodiments, a suitable base is K2 CO3 . In some embodiments, a suitable temperature for a suitable time is about room temperature for about 3 hours. In some embodiments, the compound is chlorinated under chlorinated conditionsIX - 2 converted to acid chlorideIX - 3 . In some embodiments, chlorination conditions include the use of (chloromethylene)dimethyliminium chloride and a base in a suitable solvent at a suitable temperature. In some embodiments, a suitable base is anhydrous K2 CO3 . In some embodiments, a suitable temperature is about 0°C. In some embodiments, a suitable solvent is toluene. In some embodiments, addingIX - 2 and stirring the mixture at a suitable temperature for a suitable time to produceIX - 3 . In some embodiments, a suitable temperature for a suitable time is about room temperature for about 0.5 to about one hour. In some embodiments, the compounds described herein are prepared as outlined in Scheme 10.process 10
Figure 02_image231
In scheme 10, substituent Y, X1 、X2 、X3 、X4 , R1 , R2 , R6 , R8 and m are as described herein. In some embodiments, X2 for C-R2 , X3 For C-H and each X4 for C-H. In some embodiments, the alcoholx - 1 React under suitable halogenation conditions to produce alkyl halidesx - 2 . In some embodiments, suitable halogenation conditions are bromination conditions comprising the use of CBr in a suitable solvent at a suitable initial temperature4 , followed by PPh in a suitable solvent at a suitable temperature3 last for the right amount of time. In some embodiments, a suitable solvent is a halogenated solvent, such as DCM. In some embodiments, a suitable initial temperature is about 0°C. In some embodiments, adding PPh3 A suitable temperature and time thereafter is about 0°C for about one hour. In some embodiments, the reaction is further warmed to about room temperature for about overnight. In some embodiments, ammonium chloride is amidex - 3 , to get the compoundx - 4 . Suitable acylation conditions include, but are not limited to, using a suitable base, such as pyridine, in a suitable solvent, such as DCM or toluene, at a suitable temperature, such as about 0°C. In some embodiments, the acyl chloride is added in a suitable solvent at a suitable temperature for a suitable amount of time. In some embodiments, a suitable solvent is toluene. In some embodiments, a suitable temperature is about 0°C, followed by warming to room temperature for about overnight. In some embodiments, bromide is used in a suitable solvent, such as DMF, at a suitable temperaturex - 2 rightx - 4 N-Alkylation and Preparation of Compounds with Suitable Basesx - 5 Lasts for a suitable amount of time. Suitable bases include NaH. In some embodiments, the compound is pretreated with a suitable base at a suitable temperature, such as at about 0°C to about room temperaturex - 4 for a suitable amount of time, such as about two hours, after which bromide is addedx - 2 . In some embodiments, adding bromidex - 2 A suitable time and temperature thereafter is about room temperature for about overnight. In some embodiments, Y contains a protected alcohol. In some embodiments, Y is protected with a silyl ether. In some embodiments, the protecting group is removed using suitable deprotection conditions, including suitable solvents, temperatures and times, to generate the free alcohol, yieldingx - 5 . In some embodiments, suitable deprotection conditions include the use of fluoride reagents. In some embodiments, the fluoride reagent is NH4 F. In some embodiments, a suitable solvent is methanol. In some embodiments, a suitable time at a suitable temperature is about overnight at about 60°C. In some embodiments, the compounds described herein are prepared as outlined in Scheme 11.process 11
Figure 02_image233
In scheme 11, substituent Y, X1 、X2 、X3 、X4 , R1 , R2 , R4 , R5 , R6 , R8 and m are as described herein. In some embodiments, X2 for C-R2 , X3 For C-H and each X4 for C-H. In some embodiments, X is a suitable cross-coupling substituent. In some embodiments, X is a halide. In some embodiments, X is chlorine, bromine or iodine. In some embodiments, the compoundXI - 1 Reaction with a suitable source of acetylene under suitable metal-catalyzed cross-coupling reaction conditions givesXI - 2 . In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, a suitable source of acetylene is trimethylsilylacetylene. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(PPh3 )2 Cl2 , a copper catalyst and a suitable base for a suitable time and at a suitable temperature. In some embodiments, the copper catalyst is CuI. In some embodiments, the base is an amine base, such as TEA. In some embodiments, a suitable time and suitable temperature are about 6 hours at about 90°C. In some embodiments, following cross-coupling, the TMS group is removed under suitable deprotection conditions to formXI - 2 , such conditions include suitable solvent, temperature and time. In some embodiments, suitable deprotection conditions include the use of fluoride reagents. In some embodiments, the fluoride reagent is NH4 F. In some embodiments, a suitable solvent is methanol. In some embodiments, a suitable time at about 60°C is about one hour. In some embodiments, acetyleneXI - 2 Reaction with a suitable heteroaromatic halide under suitable metal-catalyzed cross-coupling reaction conditions givesXI - 3 . In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable heteroaromatic halides are pyrazolyl halides. In some embodiments, the heteroaromatic halide is a heteroaromatic iodide. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(PPh3 )2 Cl2 , a copper catalyst and a suitable base for a suitable time and at a suitable temperature. In some embodiments, the copper catalyst is CuI. In some embodiments, the base is an amine base, such as TEA. In some embodiments, a suitable time and a suitable temperature are about one hour at about 80°C to about 90°C or about 70°C to about 90°C. In some embodiments, Y contains a protected alcohol. In some embodiments, Y is protected with a silyl ether. In some embodiments, the protecting group is removed using suitable deprotection conditions, including suitable solvents, temperatures and times, to generate the free alcohol, yieldingXI - 3 . In some embodiments, suitable deprotection conditions include the use of aqueous HCl. In some embodiments, suitable solvents are water, THF, methanol, or a combination of solvents. In some embodiments, a suitable time at a suitable temperature is from about 30 minutes to about 1 hour at about 0°C to about room temperature. In some embodiments, compounds are prepared as described in the Examples.specific term Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term "including" and other forms such as "include", "includes" and "included" is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. As used herein, C1 -Cx including C1 -C2 、C1 -C3 ...C1 -Cx . For example only, expressed as "C1 -C4 A group of " indicates the presence of one to four carbon atoms in the moiety, ie a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Therefore, by way of example only, "C1 -C4 "Alkyl" indicates the presence of one to four carbon atoms in the alkyl group, that is, the alkyl group is selected from the group consisting of: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tertiary butyl. "Alkyl" means an aliphatic hydrocarbon group. Alkyl is branched or straight chain. In some embodiments, "alkyl" has 1 to 10 carbon atoms, ie C1 -C10 alkyl. Whenever appearing herein, numerical ranges such as "1 to 10" refer to each integer in the given range; for example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to (and including) 10 carbon atoms, but the definition of the present invention also covers the term "alkane" which does not specify a numerical range base" exists. In some embodiments, alkyl is C1 -C6 alkyl. In one aspect, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, second-butyl or third-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, or hexyl. "Alkylene" means a divalent alkyl group. Any of the above-mentioned monovalent alkyl groups may be an alkylene group by abstracting a second hydrogen atom from the alkyl group. In some embodiments, the alkylene group is C1 -C6 Alkylene. In other embodiments, the alkylene group is C1 -C4 Alkylene. In certain embodiments, the alkylene group contains one to four carbon atoms (eg, C1 -C4 alkylene). In other embodiments, the alkylene group contains 1 to 3 carbon atoms (eg, C1 -C3 alkylene). In other embodiments, the alkylene group contains one to two carbon atoms (eg, C1 -C2 alkylene). In other embodiments, the alkylene group contains one carbon atom (eg, C1 alkylene). In other embodiments, the alkylene group contains two carbon atoms (eg, C2 alkylene). In other embodiments, the alkylene group contains two to four carbon atoms (eg, C2 -C4 alkylene). Typical alkylene groups include (but are not limited to) -CH2 -, -CH(CH3 )-, -C(CH3 )2 -, -CH2 CH2 -, -CH2 CH(CH3 )-, -CH2 C(CH3 )2 -, -CH2 CH2 CH2 -, -CH2 CH2 CH2 CH2 - and its like. "Deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced by deuterium. The term "alkenyl" refers to a type of alkyl in which at least one carbon-carbon double bond is present. In one embodiment, alkenyl has the formula -C(R)=CR2 , wherein R refers to the rest of the alkenyl, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, the alkenyl group is selected from the group consisting of ethenyl (ie, vinyl), propenyl (ie, allyl), butenyl, pentenyl, pentadienyl, and similar. Non-limiting examples of alkenyl groups include -CH=CH2 、-C(CH3 )=CH2 、-CH=CHCH3 、-C(CH3 )=CHCH3 and -CH2 CH=CH2 . The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkynyl has the formula -C≡C-R, where R refers to the rest of the alkynyl. In some embodiments, R is H or alkyl. In some embodiments, the alkynyl group is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3 、-C≡CCH2 CH3 、-CH2 C≡CH. "Alkoxy" means an (alkyl)O- group in which alkyl is as defined herein. The term "alkylamine" refers to -N(alkyl)x hthe y A group where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0. The term "aromatic" refers to a planar ring with a delocalized π-electron system containing 4n+2π electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl groups ("aryl" such as phenyl) and heterocyclic aryl groups (or "heteroaryl" or "heteroaromatic") such as pyridine. The term includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of carbon or nitrogen atoms) groups. The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocycles from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom different from carbon. In some embodiments, at least one of the two rings of the bicyclic carbocycle is aromatic. In some embodiments, both rings of the bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl. As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is C6 -C10 Aryl. Depending on the structure, aryl groups are monoradicals or diradicals (ie, aryl groups). The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical in which each of the atoms forming the ring (ie, backbone atoms) is a carbon atom. In some embodiments, cycloalkyl is a spiro or bridged compound. In some embodiments, a cycloalkyl group is optionally fused to an aromatic ring with the point of attachment at a carbon other than a carbon atom of the aromatic ring. Cycloalkyl includes groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro [2.2] Pentyl, nor-pentyl and bicyclo[1.1.1]pentyl. In some embodiments, cycloalkyl is C3 -C6 Cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, nor-bicyclo[2.2.1]heptyl), nor-alkenyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1] ] Heptyl and the like. The term "halo", or alternatively, "halogen" or "halide" means fluorine, chlorine, bromine or iodine. In some embodiments, halo is fluoro, chloro, or bromo. The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. In one aspect, fluoroalkyl is C1 -C6 Fluoroalkyl. The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, fluoroalkyl is C1 -C6 Fluoroalkyl. In some embodiments, the fluoroalkyl group is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and similar. The term "heteroalkyl" refers to one or more of the backbone atoms of an alkyl group selected from atoms other than carbon, such as oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur or combinations thereof alkyl. A heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. In one aspect, heteroalkyl is C1 -C6 Heteroalkyl. The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryl) and heterocycloalkyl rings (also known as heteroalicyclic group), wherein each heteroatom in the ring is selected from O, S and N, wherein each heterocyclic group has 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, the heterocycle is a monocyclic, bicyclic, polycyclic, spirocyclic or bridged compound. Non-aromatic heterocyclyl (also known as heterocycloalkyl) includes rings having 3 to 10 atoms in their ring system, and aromatic heterocyclyl includes rings having 5 to 10 atoms in their ring system . Heterocyclyl includes benzofused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, oxazolidinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl yl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thiacyclyl Butyl, homopiperidinyl, oxepinyl, thiepanyl, oxazanyl, diazanyl, thiazepinyl, 1,2,3,6 -tetrahydropyridyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-di Oxylanyl, pyrazolinyl, dithianyl, dithiophenyl, dihydropyranyl, dihydrothienyl, dihydrofuryl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3 -Azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, indoline-2-one, isoindoline-1-one, iso Indoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindole Line-1,3-disulfinyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d] Thiazol-2(3H)-onyl and quinazinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl , Isothiazolyl, Pyrrolyl, Quinolinyl, Isoquinolyl, Indolyl, Benzimidazolyl, Benzofuryl, Zeolinyl, Indazolyl, Indorazinyl, Phthalazinyl, Pyridazine base, triazinyl, isoindolyl, pteridyl, purinyl, oxadiazolyl, thiadiazolyl, furanyl, benzofuranyl, benzothienyl, benzothiazolyl, benzo Oxazolyl, quinazolinyl, quinoxalinyl, phenidyl and furopyridyl. The aforementioned groups are C-attached (or C-linked) orN - Connected (where possible). For example, groups derived from pyrrole include pyrrol-1-yl (N -connection) or pyrrol-3-yl (C-connection) both. Heterocyclyl includes benzofused ring systems. Non-aromatic heterocycles are optionally substituted with one or two pendant oxy (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic. The term "heteroaryl", or alternatively, "heteroaromatic" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl include monocyclic heteroaryl and bicyclic heteroaryl. Monocyclic heteroaryl groups include pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, iso Thiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl and furanyl. Bicyclic heteroaryls include indoxazine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinozine, quinoline, isoquinoline, zezoline, phthalazine, quinazoline, quinoline oxoline, 1,8-phenidine and pteridine. In some embodiments, heteroaryl groups contain 0 to 4 N atoms in the ring. In some embodiments, heteroaryl groups contain 1 to 4 N atoms in the ring. In some embodiments, heteroaryl groups contain 0 to 4 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms in the ring. In some embodiments, heteroaryl groups contain 1 to 4 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms in the ring. In some embodiments, heteroaryl is C1 -C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is C1 -C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is C6 -C9 heteroaryl. A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl , Thiomorpholino, piperazinyl, piperidin-2-one, pyrrolidin-2,5-disulfinyl, pyrrolidine-2,5-dione, pyrrolidinone, imidazolidine group, imidazolidin-2-one group or thiazolidin-2-one group. The term heteroalicyclic also includes all cyclic forms of carbohydrates including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one aspect, heterocycloalkyl is C2 -C10 Heterocycloalkyl. In one aspect, heterocycloalkyl is C4 -C10 Heterocycloalkyl. In some embodiments, heterocycloalkyl groups contain 0 to 2 N atoms in the ring. In some embodiments, a heterocycloalkyl group contains 0 to 2 N atoms, 0 to 2 O atoms, and 0 to 1 S atom in the ring. The terms "bond" or "single bond" refer to a chemical bond between two atoms or two parts when the atoms joined by the bond are considered part of a larger substructure. In one aspect, when a group described herein is a bond, the mentioned group is absent, thereby allowing a bond to form between the remaining identified groups. The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is a generally recognized chemical entity embedded or attached to a molecule. The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more other groups individually and independently selected from D, halogen, - CN, -NH2 , -NH(alkyl), -N(alkyl)2 , -OH, -CO2 H, -CO2 Alkyl, -C(=O)NH2 , -C(=O)NH(alkyl), -C(=O)N(alkyl)2 , -S(=O)2 NH2 , -S(=O)2 NH(alkyl), -S(=O)2 N(alkyl)2 , Alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio , arylthio, alkyl phosphonium, aryl phosphonium, alkyl phosphonium and aryl phosphonium. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2 , -NH(CH3 ), -N(CH3 )2 , -OH, -CO2 H, -CO2 (C1 -C4 Alkyl), -C(=O)NH2 , -C(=O)NH(C1 -C4 Alkyl), -C(=O)N(C1 -C4 alkyl)2 , -S(=O)2 NH2 , -S(=O)2 NH(C1 -C4 Alkyl), -S(=O)2 N(C1 -C4 alkyl)2 、C1 -C4 Alkyl, C3 -C6 Cycloalkyl, C1 -C4 Fluoroalkyl, C1 -C4 Heteroalkyl, C1 -C4 Alkoxy, C1 -C4 Fluoroalkoxy, -SC1 -C4 Alkyl, -S(=O)C1 -C4 Alkyl and -S(=O)2 C1 -C4 alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2 , -OH, -NH(CH3 ), -N(CH3 )2 、-CH3 、-CH2 CH3 、-CF3 、-OCH3 and-OCF3 . In some embodiments, a substituted group is substituted with one or both of the preceding groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include pendant oxy (=O). The term "acceptable" as used herein with respect to a formulation, composition or ingredient means having no persistent deleterious effect on the overall health of the individual being treated. As used herein, the term "modulates" means interacting directly or indirectly with a target in order to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or Extend the activity of the target. As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions of agonists, partial agonists, inverse agonists, antagonists, down-regulators, or combinations thereof. In some embodiments, modulators are agonists. As used herein, the terms "administer", "administering", "administration" and similar terms refer to a drug that can be used to achieve delivery of a compound or composition to a desired site of biological action. Methods. Such methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art are familiar with techniques for administering the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally. As used herein, the term "co-administration" or its analogy is meant to encompass administration of selected therapeutic agents to a single patient and is intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times. As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of an administered agent or compound sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. Outcomes include alleviation and/or alleviation of a sign, symptom or cause of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to produce a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any particular situation is optionally determined using techniques such as dose escalation studies. As used herein, the term "enhance/enhancing" means to increase or prolong the potency or duration of a desired effect. Thus, in reference to enhancing the effect of a therapeutic agent, the term "enhancing" refers to the ability to increase or prolong the potency or duration of the effect of another therapeutic agent on a system. As used herein, "enhancing effective amount" refers to an amount sufficient to enhance the effect of other therapeutic agents in the desired system. As used herein, the term "pharmaceutical combination" means a product resulting from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, eg, a compound described herein, or a pharmaceutically acceptable salt thereof, and an adjuvant are both administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as a compound described herein or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient simultaneously, concurrently or sequentially in the form of separate entities without a specific intervening time limit, wherein such administration provides effective levels of both compounds in the patient. The latter also applies to mixture therapy, eg administration of three or more active ingredients. The terms "kit" and "article" are used synonymously. The term "individual" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class of mammals: humans, non-human primates (such as chimpanzees and other ape and monkey species); farm animals such as cattle, horses, sheep, goats, pigs ; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents such as rats, mice and guinea pigs and the like. In one aspect, the mammal is a human. As used herein, the term "treat/treating/treatment" includes prophylactically and/or therapeutically alleviating, alleviating or ameliorating at least one symptom of a disease or condition; preventing other symptoms; inhibiting a disease or condition, e.g. using To arrest the development of a disease or condition; to alleviate a disease or condition; to cause regression of a disease or condition; to alleviate the symptoms caused by a disease or condition; or to cause the symptoms of a disease or condition to cease.pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients which facilitate processing of the active compound into preparations for pharmaceutical use. Proper formulation will depend upon the route of administration chosen. An overview of the pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co. , Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L. eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins1999), on Such disclosures are incorporated herein by reference. In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. Administration of the compounds and compositions described herein can be accomplished by any method that enables delivery of the compounds to the site of action. Such methods include, but are not limited to, delivery via enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (injection or infusion, including intraarterial, intracardiac , intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, transdermal Buccal and topical (including epidermal, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, but the most suitable route may depend, for example, on the condition and condition of the recipient. By way of example only, the compounds described herein can be administered to an area in need of treatment, eg, by local infusion during surgery, topical application such as a cream or ointment, injection, catheter or implant surface. Administration may also be by direct injection at the site of a diseased tissue or organ. In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units, such as capsules, cachets, or lozenges, each containing a predetermined amount of the active ingredient; in powder or granule form; in aqueous or non-aqueous liquid in the form of solutions or suspensions in; or in the form of oil-in-water liquid emulsions or water-in-oil liquid emulsions. In some embodiments, the active ingredient is presented as a bolus, lick or paste. Pharmaceutical compositions which can be used orally include lozenges, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, inert diluent, or lubricating, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquers and suitable Organic solvent or solvent mixture. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, eg, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be in powder form immediately before use or after the addition of a sterile liquid carrier (e.g., physiological saline or sterile pyrogen-free water) is simply required. Store under freeze-dried (lyophilized) conditions. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described. Pharmaceutical compositions for parenteral administration include aqueous and nonaqueous (oily) sterile injectable solutions which may contain antioxidants, buffers, bacteriostats, and solutes to render the formulation isotonic with the blood of the intended recipient; Aqueous and non-aqueous sterile suspensions including suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil; or synthetic fatty acid esters, such as ethyl oleate or triglycerides; or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Pharmaceutical compositions can also be formulated as depot preparations. Such long-acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, the compounds may be formulated, for example, with suitable polymeric or hydrophobic materials, eg, as emulsions in acceptable oils, or with ion exchange resins, or as sparingly soluble derivatives, eg, sparingly soluble salts. For buccal or sublingual administration, the compositions may take the form of troches, lozenges, tablets or gels formulated in conventional manner. Such compositions may contain the active ingredient in a palatable base such as sucrose and acacia or tragacanth. Pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol or other glycerides. Pharmaceutical compositions can be administered topically, ie by non-systemic administration. This includes topical application of a compound of the invention to the epidermis or buccal cavity, and instillation of the compound into the ears, eyes and nose so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration. Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetrating the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes and suitable for administration to the eye. , drops for ear or nose. For topical administration, the active ingredient may comprise from 0.001% w/w to 10% w/w, eg 1% w/w to 2% w/w, by weight of the formulation. Pharmaceutical compositions for administration by inhalation are conveniently delivered by insufflator, pressurized pack in a nebulizer or other suitable method of delivering an aerosol spray. Pressurized packages may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the pharmaceutical formulation may take the form of a dry powder composition, eg a powder mix of the compound and a suitable powder base such as lactose or starch. Powder compositions may be presented in unit dosage form, eg, capsules, cartridges, gelatin or blister packs, from which the powder may be administered by means of an inhaler or insufflator. In some embodiments, the compounds disclosed herein are formulated in such a way that delivery of the compounds to specific regions of the gastrointestinal tract is achieved. For example, the compounds disclosed herein are formulated for oral delivery with bioadhesive polymers, pH-sensitive coatings, time-dependent biodegradable polymers, microbiota activation systems, and the like, in order to affect compound delivery to Specific areas of the gastrointestinal tract. In some embodiments, the compounds disclosed herein are formulated such that the compounds are controlled release. Controlled release refers to the release of a compound described herein from the dosage form into which it is incorporated over an extended period of time according to a desired profile. Controlled-release profiles include, for example, sustained-release, extended-release, pulsed-release and delayed-release profiles. Controlled release compositions deliver an agent to an individual over a longer period of time according to a predetermined profile than immediate release compositions. Such release rates can provide therapeutically effective levels of the agent over a longer period of time than conventional rapid release dosage forms, and thus provide a longer period of drug response while minimizing side effects. Such longer response periods provide many inherent benefits not available with corresponding short-acting, immediate release formulations. Methods of delivering intact therapeutic compounds to specific regions of the gastrointestinal tract (e.g., the colon) include: (i) Coating with polymers: intact molecules can be regenerated in the environment by coating the drug molecule with a suitable polymer that only degrades in the colon. Delivered to the colon without absorption in the upper intestine. (ii) Coating with pH sensitive polymers: Most enteric and colon targeted delivery systems are based on tablets or pellets filled in conventional hard gelatin capsules. The most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as Eudragit® S, more specifically Eudragit® L and Eudragit® S. Eudragit® L100 and S 100 are copolymers of methacrylic acid and methyl methacrylate. (iii) coated with biodegradable polymers; (iv) embedded in matrices; (v) embedded in biodegradable matrices and hydrogels; (vi) embedded in pH sensitive matrices (vii) timed release systems; (viii) redox sensitive polymers; (ix) bioadhesive systems; (x) coated with microparticles; (xi) osmotically controlled drug delivery; Another approach to a controlled release system involves embedding the drug in a polymer matrix to trap it and release it in the colon. Such matrices may be pH sensitive or biodegradable. Matrix-based systems, such as multi-matrix (MMX) delayed-release lozenges will ensure drug release in the colon. Other medical approaches to target the delivery of therapeutic agents to specific regions of the gastrointestinal tract are known. Chourasia MK, Jain SK, Pharmaceutical approaches to colon targeted drug delivery systems., J Pharm Pharm Sci. 2003 Jan-Apr;6(1):33-66. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific drug-delivery systems Crit Rev Ther Drug Carrier Syst. 2007;24(2):147-202. Kumar P, Mishra B. Colon targeted drug delivery systems--an overview. Curr Drug Deliv. 2008 Jul;5(3):186-98. Van den Mooter G. Colon drug delivery. Expert Opin Drug Deliv. 2006 Jan;3(1):111-25. Seth Amidon, Jack E. Brown, and Vivek S. Dave, Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches, AAPS PharmSciTech. 2015 Aug; 16(4): 731-741. It should be understood that, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may also include other agents known in the art having regard to the type of formulation in question, such as those suitable for oral administration Compounds and compositions therewith may include flavoring agents.Dosing method and treatment plan In one embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is used in the manufacture of a medicament for the treatment of a disease or condition in a mammal that would benefit from administration of an FXR agonist. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involve administering to the mammal a pharmaceutical composition comprising at least one of the herein described The compound or its pharmaceutically acceptable salt, active metabolite, prodrug or pharmaceutically acceptable solvate. Disclosed herein are methods of administering FXR agonists as well as additional therapeutic agents. In some embodiments, the additional therapeutic agent comprises a therapeutic agent for the treatment of diabetes or a diabetes-related disorder or condition, alcoholic or non-alcoholic liver disease, an inflammation-related intestinal condition, or a cell proliferative disorder. In certain embodiments, compositions containing compounds described herein are administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, compositions are administered to a patient with an existing disease or condition in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and/or dose ranging clinical trials. In prophylactic applications, a composition containing a compound described herein is administered to a patient susceptible to or at risk of a particular disease, disorder or condition. Such amount is defined as a "prophylactically effective amount or dose". In this use, the precise amount will also depend on the patient's state of health, weight, and the like. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment comprises administering to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission a pharmaceutical composition to prevent recurrence of symptoms of the disease or condition, the pharmaceutical composition Comprising a compound described herein, or a pharmaceutically acceptable salt thereof. In certain embodiments where the patient's condition does not improve, the compound is administered chronically, that is, for a longer period of time, including the entire duration of the patient's life, to ameliorate or otherwise control or limit the patient's condition, at the discretion of the physician. symptoms of a disease or condition. In certain embodiments where the patient's condition improves, the dose of drug administered is temporarily reduced or temporarily suspended for a period of time (ie, a "drug holiday"). In particular embodiments, the length of the drug holiday is between 2 days and 1 year, including for example only 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days days, 28 days or more than 28 days. Dosage reductions during drug holidays are only for example 10% to 100%, including only for example 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100%. Once the patient's condition improves, a maintenance dose is administered as necessary. Subsequently, in certain embodiments, the dose or frequency of administration, or both, is reduced based on symptoms to such an extent that the improved disease, disorder or condition is maintained. However, in certain embodiments, patients require intermittent treatment on a long-term basis to prevent any recurrence of symptoms. The amount of administered agent corresponding to such amount varies depending on factors such as the particular compound, the disease condition and its severity, individual characteristics (e.g. body weight, sex) or the subject requiring treatment, however it is based on the circumstances surrounding the case. It is determined by the particular circumstances, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the individual or subject being treated. In general, however, dosages for adult treatment usually range from 0.01 mg to 5000 mg per day. In one aspect, dosages for adult treatment range from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose may conveniently be presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example in sub-doses of two, three, four or more times per day. In one embodiment, a suitable daily dosage of a compound described herein, or a pharmaceutically acceptable salt thereof, is about 0.01 to about 50 mg per kilogram of body weight. In some embodiments, the daily dose or amount of active in the dosage form is lower or higher than the range indicated herein, based on the many variables associated with individual treatment regimens. In various embodiments, the daily and unit dosage varies depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the The severity of the disease or condition and the physician's judgment. Toxicity and therapeutic efficacy of such treatment regimens are determined by standard medical procedures in cell culture or experimental animals, including but not limited to LD50 and ED50 The determination. The dose ratio between toxic and therapeutic effects is the therapeutic index and it is expressed as LD50 with ED50 ratio between. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dosage ranges and/or therapeutically effective unit dosage amounts for mammals, including humans. In some embodiments, the daily dosage amount of the compound described herein is at the ED including the ED with minimal toxicity.50 within the range of circulating concentrations. In certain embodiments, depending on the dosage form employed and the route of administration employed, the daily dosage range and/or the unit dosage amount varies within this range. Any of the foregoing aspects is administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof: (a) systemically to a mammal; and/or (b) orally administered to a lactation and/or (c) intravenous administration to mammals; and/or (d) administration to mammals by injection; and/or (e) topical administration to mammals; and/or (f) non-systemic administration Other embodiments are administered locally or locally to a mammal. Any of the foregoing aspects are further embodiments comprising a single administration of an effective amount of the compound, including wherein (i) the compound is administered to the mammal once a day or (ii) the compound is administered to the mammal in one day Multiple other examples. Any of the foregoing aspects are other embodiments comprising multiple administrations of an effective amount of the compound, including (i) continuous or intermittent administration of the compound in single doses; (ii) intervals between multiple doses. The timing is every 6 hours; (iii) administering the compound to the mammal every 8 hours; (iv) administering the compound to the mammal every 12 hours; (v) other embodiments of administering the compound every 24 hours. In additional or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound administered is temporarily reduced; at the end of the drug holiday, the administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. In certain instances, it may be desirable to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents. In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit by itself, but in combination with other therapeutic agents, enhances the overall effect on the patient). therapeutic benefit). Alternatively, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has a therapeutic benefit. In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein a compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent Modulating different aspects of the disease, disorder or condition being treated, thereby providing an overall benefit that is better than administering either therapeutic agent alone. In any event, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient can be additive of the two therapeutic agents, or the patient can experience a synergistic benefit. In certain embodiments, when a compound disclosed herein is administered in combination with one or more other agents, such as other therapeutically effective drugs, adjuvants, or the like, in formulating pharmaceutical compositions and/or in therapeutic regimens Various therapeutically effective doses of the compounds disclosed herein will be employed. Therapeutically effective doses of drugs and other agents used in combination treatment regimens are optionally determined in a manner analogous to that described above for the active agents themselves. In addition, the prophylactic/therapeutic methods described herein encompass the use of metronomic dosing, ie, providing more frequent, lower doses to minimize toxic side effects. In some embodiments, the combination treatment regimen encompasses administration of a compound described herein, or a pharmaceutically acceptable salt thereof, initiated before, during, or after treatment with the second agent described herein and continued until treated with the second agent Treatment regimen during treatment or at any time after completion of treatment with the second agent. It also includes treatments wherein a compound described herein, or a pharmaceutically acceptable salt thereof, and a second agent used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination therapy further includes periodic therapy beginning and ending at various times to assist in the clinical management of the patient. It is to be understood that dosage regimens for the treatment, prevention or amelioration of the condition for which relief is sought will be adjusted according to a variety of factors such as the disease, disorder or condition in which the individual suffers; the age, weight, sex, diet and medical condition of the individual . Thus, in some cases, the actual dosage regimen employed varies and, in some embodiments, deviates from the dosage regimen described herein. For the combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug used, the specific drug used, the disease or condition being treated, and the like. In other embodiments, when co-administered with one or more other therapeutic agents, a compound provided herein and one or more other therapeutic agents are administered simultaneously or sequentially. In combination therapy, multiple therapeutic agents, one of which is one of the compounds described herein, are administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are provided only, eg, in a single unified form, or in multiple forms, eg, in a single pill or in two separate pills. Administration of the compounds described herein, or pharmaceutically acceptable salts thereof, and combination therapies before, during, or after the onset of a disease or condition, and the timing of administration of compositions containing the compounds will vary. Thus, in one embodiment, the compounds described herein are used prophylactically and are administered continuously to individuals prone to a condition or disease to prevent the disease or condition from occurring. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In particular embodiments, the compounds described herein are administered as soon as practicable after the onset of a detected or suspected disease or condition and continued for as long as necessary to treat the disease. In some embodiments, the duration of treatment required varies and is adjusted to suit the specific needs of each individual. For example, in certain embodiments, a compound described herein, or a formulation containing the compound, is administered for at least 2 weeks, from about 1 month to about 5 years. In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent for the treatment of diabetes or a diabetes-related disorder or condition. In some instances, additional therapeutic agents include statins, insulin-sensitizing drugs, insulin secretagogues, alpha-glucosidase inhibitors, GLP agonists, DPP-4 inhibitors (such as sitagliptin ( sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, teneligliptin, alogliptin , gemiglptin or dutoglpitin), catecholamines (such as epinephrine, norepinephrine, or dopamine), peroxisome proliferator-activated receptor (PPAR)-gamma agonists (such as Thiazolidinedione (TZD) [such as pioglitazone, rosiglitazone, rivoglitazone, or troglitazone], aleglitazar, faglita farglitazar, muraglitazar or tesaglitazar, or a combination thereof. In some instances, the statin is an HMG-CoA reductase inhibitor. In other instances, additional therapeutic agents include fish oils, fibrates, vitamins such as niacin, retinoic acid (eg, 9-cis retinoic acid), nicotinamide nucleoside, or analogs thereof, or combinations thereof. In some cases, nicotinamide nucleoside or its analogs promote the production of NAD+ , the NAD+ is a substrate for a variety of enzymatic reactions, including p450, which is a target of FXR (see, e.g., Yang et al.,J. Med. Chem. 50:6458-61, 2007). In some embodiments, FXR agonists are administered in combination with additional therapeutic agents for the treatment of diabetes or diabetes-related disorders or conditions, such as statins, insulin sensitizing drugs, insulin secretagogues, alpha-glucosidase inhibitors agents, GLP agonists, DPP-4 inhibitors (such as sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, tiagliptin, alogliptin, gem agliptin or duogliptin), catecholamines (such as epinephrine, norepinephrine, or dopamine), peroxisome proliferator-activated receptor (PPAR)-gamma agonists (such as thiazolidinediones (TZD) [ Such as pioglitazone, rosiglitazone, riglitazone, or troglitazone], aglitaza, faglitaza, moglitaza, or tiglitazone) or combinations thereof. In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent, such as fish oil, fibrates, vitamins such as niacin, retinoic acid, for the treatment of diabetes or a diabetes-related disorder or condition. (such as 9-cis retinoic acid), nicotinamide nucleoside or its analogue) or a combination thereof. In some embodiments, the FXR agonist is administered in combination with a statin, such as an HMG-CoA reductase inhibitor, fish oil, fibrates, niacin, or a combination thereof, for the treatment of dyslipidemia. In other embodiments, FXR agonists are administered in combination with vitamins, such as retinoic acid, for the treatment of diabetes and diabetes-related disorders or conditions, such as reducing elevated body weight and/or reducing elevated body weight caused by food intake. High blood sugar. In some embodiments, the farnesoid X receptor agonist is administered with at least one additional therapy. In some embodiments, at least one additional therapy is a glucose lowering agent. In some embodiments, at least one additional therapy is an anti-obesity agent. In some embodiments, at least one additional therapy is selected from the group consisting of peroxisome proliferator-activated receptor (PPAR) agonists (gamma, dual, or pan), dipeptidyl peptidase (IV) inhibitors, Glucagon-like peptide-1 (GLP-I) analogs, insulin or insulin analogs, insulin secretagogues, sodium glucose cotransporter 2 (SGLT2) inhibitors, glucophage, human amylin analogs , biguanides, alpha-glucosidase inhibitors, meglitinide, thiazolidinediones, and sulfonylureas. In some embodiments, the at least one additional therapy is metformin, sitagliptin, saxagliptin, repaglinide, nateglinide, exenatide, liralu liraglutide, insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin protamine and glucagon-like peptide 1 or any combination thereof. In some embodiments, at least one additional therapy is a lipid-lowering agent. In certain embodiments, at least one additional therapy is administered concurrently with the farnesoid X receptor agonist. In certain embodiments, at least one additional therapy is administered less frequently than the farnesoid X receptor agonist. In certain embodiments, at least one additional therapy is administered more frequently than the farnesoid X receptor agonist. In certain embodiments, at least one additional therapy is administered prior to administration of the farnesoid X receptor agonist. In certain embodiments, at least one additional therapy is administered after administration of the farnesoid X receptor agonist. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is administered in combination with chemotherapy, anti-inflammatory agents, radiation therapy, monoclonal antibodies, or combinations thereof. In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent for the treatment of alcoholic or nonalcoholic liver disease. In some embodiments, additional therapeutic agents include antioxidants, corticosteroids, anti-tumor necrosis factor (TNF), or combinations thereof. In some embodiments, the FXR agonist is administered in combination with additional therapeutic agents for the treatment of alcoholic or non-alcoholic liver disease, such as antioxidants, corticosteroids, anti-tumor necrosis factor (TNF), or combinations thereof. In some embodiments, an FXR agonist is administered in combination with an antioxidant, a vitamin precursor, a corticosteroid, an anti-tumor necrosis factor (TNF), or a combination thereof for the treatment of alcoholic or non-alcoholic liver disease. In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent for the treatment of an inflammation-related intestinal condition. In some instances, additional therapeutic agents include antibiotics (such as metronidazole, vancomycin, and/or fidaxomicin), corticosteroids, or other anti-inflammatory or immunomodulatory therapies. In some instances, FXR agonists are administered in combination with additional therapeutic agents, such as antibiotics, corticosteroids, or other anti-inflammatory or immunomodulatory therapies for treating inflammation-related intestinal conditions. In some instances, the FXR agonist is administered in combination with metronidazole, vancomycin, fidaxomicin, corticosteroids, or combinations thereof for the treatment of intestinal conditions associated with inflammation. As discussed above, inflammation is sometimes associated with pseudomembranous colitis. In some cases, pseudomembranous colitis is associated with bacterial overgrowth such as Clostridium difficile (C . dificile ) associated with overgrowth). In some embodiments, an FXR agonist is administered in combination with an antibiotic, such as metronidazole, vancomycin, fidaxomicin, or a combination thereof, for the treatment of inflammation associated with bacterial overgrowth (e.g., pseudomembranous colon inflammation). In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent for the treatment of a cell proliferative disorder. In some embodiments, additional therapeutic agents include chemotherapeutics, biotherapeutics (e.g., antibodies such as bevacizumab, cetuximab, or panitumumab), radiation therapy agents (eg, FOLFOX, FOLFIRI, CapeOX, 5-FU, folate, regorafenib, irinotecan, or oxaliplatin) or combinations thereof. In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent for the treatment of primary biliary cirrhosis. In some embodiments, the additional therapeutic agent includes ursodeoxycholic acid (UDCA). In some embodiments, a FXR agonist is administered in combination with an additional therapeutic agent, such as a chemotherapeutic, biotherapeutic, radiotherapeutic, or combination thereof, for the treatment of a cell proliferative disorder. In some instances, FXR agonists are combined with antibodies (such as bevacizumab, cetuximab, or panitumumab), chemotherapeutic agents, FOLFOX, FOLFIRI, CapeOX, 5-FU, formyltetrahydrofolate, Regorafenib, irinotecan, oxaliplatin, or combinations thereof are administered in combination for the treatment of a cell proliferative disorder.example The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein. As used above and throughout the present specification, unless otherwise indicated, the following abbreviations are understood to have the following meanings: ACN or MeCN Acetonitrile AcOH Acetate Ac Acetyl BINAP 2,2'-Bis(diphenylphosphino)- 1,1'-binaphthyl Bn benzyl BOC or Boc tert-butyl carbamate t-Bu tert-butyl Cy cyclohexyl DBA or dba dibenzylidene acetone DCE dichloroethane (ClCH2 CH2 Cl) DCM Dichloromethane (CH2 Cl2 ) DIPEA or DIEA diisopropylethylamine DMAP 4-(N,N -Dimethylamino)pyridine DME 1,2-Dimethoxyethane DMFN,N -Dimethylformamide DMAN,N -Dimethylacetamide DMSO Dimethylsulfoxide Dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene EEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro Quinoline eq Equivalent Et Ethyl Et2 O Diethyl ether EtOH Ethanol EtOAc Ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro Phosphate HMPA Hexamethylphosphamide HPLC High performance liquid chromatography KHMDS Potassium bis(trimethylsilyl)amide NaHMDS Sodium bis(trimethylsilyl)amide LiHMDS Bis(trimethylsilyl)amine Lithium LAH Lithium Aluminum Hydride LCMS Liquid Chromatography Mass Spectrometry Me Methyl MeOH Methanol MS Mass Spectrometry Ms Methanesulfonyl NBSN -Bromobutadiimide NMMN -Methyl-morpholine NMPN -Methyl-pyrrolidin-2-one NMR NMR PCC Pyridium chlorochromate Ph Phenyl PPTS Pyridium p-toluenesulfonate iPr/i-Pr Isopropyl TBS tertiary butyldimethylsilyl RP-HPLC Reverse Phase-High Pressure Liquid Chromatography TFA Trifluoroacetic Acid TEA Triethylamine THF Tetrahydrofuran TLC Thin Layer Chromatographyintermediate 1 opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexane formaldehyde
Figure 02_image235
step 1 : 8 -( 4 - Methoxy - 3 - methyl phenyl )- 1 , 4 - Dioxaspiro [ 4 . 5 ] Gui - 7 - ene Use 3 times of vacuum/N2 1,4-dioxa-spiro[4,5]dec-7-ene-8-
Figure 107108918-A0304-12-0030-1
Tetramethylethylene glycol ester (25.0 g, 93.9 mmol), 4-iodo-2-methylanisole (28.0 g, 113 mmol), 1,1'-bis(diphenylphosphino)ferrocene Palladium(II) dichloride (1.38 g, 1.89 mmol), dioxane (470 mL) and 1 M Na2 CO3 (282 mL, 282 mmol) was degassed, stirred at 50 °C for 2.5 h, and then allowed to cool to room temperature. The mixture was diluted with EtOAc (500 mL) and washed with saturated NaHCO3 (2 × 500 mL) for washing. The aqueous layer was back extracted with EtOAc (200 mL). dry (Na2 SO4 ) by combined EtOAc extracts, filtered, concentrated and purified by silica gel chromatography (0% to 5% EtOAc/hexanes) to give 8-(4-methoxy-3-methylphenyl)-1 , 4-dioxaspiro[4.5]dec-7-ene (19.9 g, 81%).1 H NMR (400 MHz, DMSO-d 6 ): δ 7.21-7.16 (m, 2H), 6.85 (d, 1H), 5.89-5.84 (m, 1H), 3.90 (s, 4H), 3.76 (s, 3H), 2.52-2.47 (m, 2H) , 2.32 (br s, 2H), 2.13 (s, 3H), 1.77 (t, 2H); LCMS: 261.1 [M+H]+ .step 2 : 8 -( 4 - Methoxy - 3 - methyl phenyl )- 1 , 4 - Dioxaspiro [ 4 . 5 ] Decane at room temperature in N2 Palladium on carbon (10 wt%, 8.08 g, 7.59 mmol) was added to 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec-7- A solution of the alkene (19.8 g, 76.1 mmol) in EtOAc (300 mL). N2 H for entry2 Balloons instead. The reaction was stirred for 4.5 hours, filtered through Celite and EtOAc, and then concentrated to afford 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5 ] Decane (18.2 g; contains 13% ketones).1 H NMR (400 MHz, DMSO-d 6 ): δ 7.00-6.95 (m, 2H), 6.81 (d, 1H), 3.91-3.84 (m, 4H), 3.73 (s, 3H), 2.49-2.42 (m, 1H), 2.11 (s, 3H) , 1.76-1.68 (m, 4H), 1.67-1.55 (m, 4H); LCMS: 263.1 [M+H]+ .step 3 : 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexanone at room temperature in N2 Formic acid (96%, 14 mL, 356 mmol) and then water (2.20 mL, 122 mmol) were added to 8-(4-methoxy-3-methylphenyl)-1,4-dioxo A solution of heterospiro[4.5]decane (18.2 g) in toluene (60 mL). The reaction was heated at 120 °C for 4 hours, allowed to cool to room temperature, and then poured into 200 mL of H2 O and 200 mL of toluene. with 200 mL H2 O, and then saturated NaHCO with 200 mL3 Wash the toluene layer. The aqueous layer was back extracted with 100 mL of toluene. dry (Na2 SO4 ) were combined toluene extracts, filtered and concentrated to give 4-(4-methoxy-3-methylphenyl)cyclohexanone (15.5 g, 88% over 2 steps) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ 7.08-7.03 (m, 2H), 6.84 (d, 1H), 3.74 (s, 3H), 3.00-2.91 (m, 1H), 2.61-2.51 (m, 2H), 2.28-2.20 (m, 2H), 2.12 (s, 3H), 2.06-1.98 (m, 2H), 1.88-1.76 (m, 2H); LCMS: 219.0 [M+H]+ .step 4 : 1 - Methoxy - 4 -( 4 -( Methoxymethylene ) Cyclohexyl )- 2 - methylbenzene in N2 A mixture of (methoxymethyl)triphenylphosphonium chloride (35.74 g, 104.3 mmol) and THF (260 mL) was cooled to -2.2 °C in an ice/brine bath. Sodium bis(trimethylsilyl)amide solution (2 M in THF, 50 mL, 100 mmol) was added dropwise via addition funnel over 12 min (internal temperature ≤ 0.6 °C) and rinsed with THF (5 mL) . The reaction was stirred for 30 minutes, and then 4-(4-methoxy-3-methylphenyl)cyclohexanone (14.5 g, 66.6 mmol) was added portionwise over 5 minutes (exotherm to 7.3 °C). The residual cyclohexanone was rinsed into the reaction with THF (20 mL). The reaction was stirred at 0 °C for 25 min, and then poured into 400 mL H2 O and 400 mL of toluene. with 400 mL H2 O washed the toluene layer, dried (Na2 SO4 ), filtered, concentrated and purified by silica gel chromatography (0% to 5% EtOAc/hexanes) to give 1-methoxy-4-(4-(methoxymethylene )cyclohexyl)-2-methylbenzene (15.6 g, 95%).1 H NMR (400 MHz, DMSO-d 6 ): δ 6.99-6.94 (m, 2H), 6.80 (d, 1H), 5.87 (s, 1H), 3.73 (s, 3H), 3.48 (s, 3H), 2.78-2.71 (m, 1H), 2.56 -2.44 (m, 1H), 2.10 (s, 3H), 2.17-2.09 (m, 1H), 2.01-1.91 (m, 1H), 1.83-1.73 (m, 2H), 1.72-1.63 (m, 1H) , 1.38-1.23 (m, 2H); LCMS: 247.1 [M+H]+ .step 5 : 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexane formaldehyde in N2 Formic acid (96%, 12.5 mL, 331 mmol) and then water (2.5 mL, 139 mmol) were added to 1-methoxy-4-(4-(methoxymethylene)cyclohexyl)- In a solution of 2-methylbenzene (16.05 g, 65.15 mmol) in toluene (130 mL). The reaction was heated at 120 °C for 2 hours, allowed to cool to room temperature, and then poured into 350 mL EtOAc and 350 mL H2 O middle. with 350 mL H2 The organic layer was washed with O and dried (Na2 SO4 ), filtered and concentrated to afford 4-(4-methoxy-3-methylphenyl)cyclohexanecarbaldehyde (15.05 g) as a 1:1 mixture of stereoisomers.step 6 : opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexane formaldehyde Aqueous sodium hydroxide (3.2 M, 31 mL, 99 mmol) was added to the crude mixture from Step 5 (14.68 g, 63.19 mmol), toluene (60 mL) and ethanol (250 mL) at room temperature. The reaction was stirred for 5.5 hours (equilibrium monitored by NMR), and then poured into 350 mL of H2 O and 350 mL EtOAc. with 350 mL H2 The organic layer was washed with O, and the aqueous layer was back extracted with 150 mL EtOAc. dry (Na2 SO4 ) combined extracts, filtered, concentrated and purified by silica gel chromatography (0% to 5% EtOAc/hexanes) to afford trans-4-(4-methoxy-3-methanol as a white solid phenyl)cyclohexanecarbaldehyde (10.17 g, 69%).1 H NMR (400 MHz, DMSO-d 6 ): δ 9.60 (s, 1H), 7.01-6.97 (m, 2H), 6.82 (d, 1H), 3.74 (s, 3H), 2.41-2.27 (m, 2H), 2.12 (s, 3H), 2.03 -1.96 (m, 2H), 1.87-1.80 (m, 2H), 1.51-1.39 (m, 2H), 1.35-1.23 (m, 2H); LCMS: 233.0 [M+H]+ . follow forintermediate 1 The described procedure synthesizes the following intermediates from the appropriate aryl halides (SM or intermediates).
Figure AA10
 Alternative Conditions: Step 1:1 EtOH, DME, 100°C, 5 hours;2 EtOH, dioxane, 100°C, overnight;3 Cs2 CO3 , Dioxane, 100°C, 6 hours;4 Pd(PPh3 )4 , 100°C, 5 hours;5 Pd(PPh3 )4 、CH3 CN/H2 O, reflux, overnight; step 2:6 MeOH;7 HCl, EtOAc; Step 3:8 PPTS, acetone, H2 O, 60°C for 10 hours;9 3 M HCl, THF, 60 °C, 3 hours to overnight; step 4:10 LiHMDS (1 M THF), 0°C or room temperature for 0.5 to 2 hours; Step 5:11 3 M HCl, THF, room temperature or 60 °C, 1 to 6 hours; step 6:12 NaOMe, MeOH, room temperature, 4 hours to overnight.intermediate 2 opposite - 4 -( 3 - chlorine - 4 - Methoxyphenyl ) Cyclohexane formaldehyde
Figure 02_image259
step 1 : 8 -( 3 - chlorine - 4 - Methoxyphenyl )- 1 , 4 - Dioxaspiro [ 4 . 5 ] Gui - 8 - alcohol Add 4-bromo-2-chloro-1-methoxy-benzene (45.00 g, 203.18 mmol) and THF (450 mL) to a 3-neck round bottom flask, add n-butyl lithium (2.5 M solution in hexane, 90.21 mL, 1.11 eq). The mixture was stirred at -78°C for 2 hours. A solution of 1,4-dioxaspiro[4.5]dec-8-one (34.91 g, 223.50 mmol) in THF (90 mL) was added dropwise to the reaction mixture. The resulting mixture was stirred at -78°C for 3 hours. use NH4 The reaction was quenched with aqueous Cl (100 mL) and extracted with EtOAc (500 mL). dry (Na2 SO4 ) organic layer, filtered and concentrated. The residue was washed with hexanes (350 mL), filtered and dried under high vacuum. The solid was triturated with hexane (15 mL), filtered and dried under high vacuum to give 8-(3-chloro-4-methoxy-phenyl)-1,4-dioxaspiro[4.5 ] Dec-8-ol (37 g, 61%).1 H NMR (400 MHz, CDCl3 ): δ 7.31 (d, 1H), 7.29 (dd, 1H), 7.10 (d, 1H), 3.90-3.92 (m, 4H), 3.89 (s, 3H), 1.99-2.02 (m, 4H), 1.70 -1.73 (m, 4H); LCMS: 281.2 [M-OH]+ .step 2 : 8 -( 3 - chlorine - 4 - Methoxyphenyl )- 1 , 4 - Dioxaspiro [ 4 . 5 ] Decane A solution of triethylsilane (19.26 g, 165.6 mmol), TFA (25.18 g, 220.8 mmol) and DCM (100 mL) was added dropwise to 8-(3-chloro-4-methoxyphenyl in a solution of -1,4-dioxaspiro[4.5]dec-8-ol (31.0 g, 110.4 mmol) and DCM (200 mL). The reaction mixture was stirred overnight at room temperature and then cooled to 0 °C. with NaHCO3 The pH of the aqueous solution was adjusted to about 8 and the mixture was extracted with DCM (2 x 100 mL). dry (Na2 SO4 ) organic layer, filtered, and concentrated to dryness to give 8-(3-chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decane (38 g, crude material) containing a small amount of 8-(3-chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]dec-7-ene. LCMS: 283.1 [M+H]+ .step 3 : 4 -( 3 - chlorine - 4 - Methoxyphenyl ) Cyclohexanone Use 3 times of vacuum/N2 8-(3-Chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decane (38.0 g, 134 mmol), formic acid (32.3 g, 672 mmol), H2 A mixture of O (4.84 g, 269 mmol) and toluene (400 mL) was degassed, stirred overnight at 130 °C, and then washed with H2 O (200 mL) and saturated NaHCO3 (200 mL) for washing. The combined aqueous layers were extracted with toluene (300 mL). dry (Na2 SO4 ) organic layer, filtered and concentrated to dryness. The residue was triturated (PE:EtOAc = 10:1, 80 mL) to give 4-(3-chloro-4-methoxyphenyl)cyclohexanone (20 g, 54%) as a light yellow solid, It contains a small amount of 3'-chloro-4'-methoxy-5,6-dihydro-[1,1'-biphenyl]-4(3h )-ketone. This solid (5.00 g, 21.12 mmol) was added to a mixture of Pd/C (10 wt.%, 820 mg, 0.77 mmol), HCl (12 M, 1.00 mL) and EtOAc (100 mL). Use 3 times of vacuum/N2 The resulting mixture was degassed by circulation, under H2 (15 psi) at room temperature for 30 minutes, filtered and then diluted with EtOAc (50 mL). Wash with water (100 mL) and wash with saturated NaHCO3 (100 mL) to wash the mixture. The aqueous phase was extracted with EtOAc (100 mL). dry (Na2 SO4 ) through the combined organic layers, filtered, and concentrated to dryness to give 4-(3-chloro-4-methoxyphenyl)cyclohexanone (4.60 g, 84%) as a yellow solid.1 H NMR (400 MHz, CDCl3 ): δ 7.24 (d, 1H), 7.09 (dd, 1H), 6.88 (d, 1H), 3.90 (s, 3H), 2.88-3.05 (m, 1H), 2.44-2.54 (m, 4H), 2.12 -2.25 (m, 2H), 1.79-1.96 (m, 2H); LCMS: 239.1 [M+H]+ .step 4 : 2 - chlorine - 1 - Methoxy - 4 -( 4 -( Methoxymethylene ) Cyclohexyl ) benzene Lithium bis(trimethylsilyl)amide (1 M, 36 mL) was added dropwise to methoxymethyl(triphenyl)phosphonium chloride (12.24 g, 35.71 mmol) and THF ( 80 mL) in the mixture. The mixture was stirred at 0°C for 2 hours. A solution of 4-(3-chloro-4-methoxy-phenyl)cyclohexanone (5.50 g, 23.04 mmol) in THF (20 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0°C for 3 hours. by H2 The reaction mixture was quenched with O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried (Na2 SO4 ), filtered, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate=20:1) to give 2-chloro-1-methoxy-4-(4-(methyl oxymethylene)cyclohexyl)benzene (5 g, 77%). LCMS: 267.1 [M+H]+ .step 5 : 4 -( 3 - chlorine - 4 - Methoxyphenyl ) Cyclohexane formaldehyde Use 3 times of vacuum/N2 2-Chloro-1-methoxy-4-(4-(methoxymethylene)cyclohexyl)benzene (5.00 g, 18.74 mmol), formic acid (4.50 g, 93.7 mmol), H2 A mixture of O (675.5 mg, 37.48 mmol) and toluene (100 mL) was degassed, stirred overnight at 130 °C, allowed to cool to room temperature, and then washed with H2 O (200 mL), washed with saturated NaHCO3 (200 mL) for washing. The combined aqueous layers were extracted with toluene (300 mL). dry (Na2 SO4 ) organic layer, filtered, and concentrated to dryness to give a mixture of cis/trans isomers as a yellow oil, 4-(3-chloro-4-methoxy-phenyl)cyclohexanecarbaldehyde (5.60 g, crude material).step 6 : opposite - 4 -( 3 - chlorine - 4 - Methoxyphenyl ) Cyclohexane formaldehyde NaOH (992.6 mg, 24.82 mmol) was dissolved in H2 The solution in O (12 mL) was added to the crude mixture from Step 5 (5.60 g, 15.51 mmol), EtOH (90 mL) and toluene (15 mL). The mixture was stirred overnight at room temperature and washed with H2 It was quenched with O (100 mL), and then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried (Na2 SO4 ), filtered and concentrated to dryness to give a residue. Purification of the residue by silica gel chromatography (petroleum ether/ethyl acetate = 20:1) and subsequent trituration with MTBE (20 mL) afforded trans-4-(3-chloro-4- Methoxyphenyl)cyclohexanecarbaldehyde (1.96 g, 49%).1 H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 7.27 (d, 1H), 7.16 (dd, 1H), 7.05 (d, 1H), 3.81 (s, 3H), 2.43 (m , 1H), 2.27-2.37 (m, 1H), 1.95-2.05 (m, 2H), 1.84 (m, 2H), 1.45 (m, 2H), 1.21-1.35 (m, 2H); LCMS: 253.1 [M +H]+ . follow forintermediate 2 The described procedure synthesized the following intermediate from 4-bromo-1-methoxy-2-methylbenzene.
Figure AA11
 Alternative conditions: Step 1: -60 °C; Step 2: 0 °C, 1 h; Step 3a: THF instead of PhMe, 80 °C, 18 h; Step 3b: No HCl, 30 psi H2 , 18 hours; Step 4: 15 hours; Step 5: 3 N HCl, THF, 60 °C, 1 hour; Step 6: THF instead of PhMe.intermediate 3 4 -( 4 - Methoxy - 3 - methyl phenyl ) Shuanghuan [ 2 . 2 . 2 ] Octane - 1 - formaldehyde
Figure 02_image263
step 1 : 4 - hydroxyl - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Ethyl cyclohexanecarboxylate Add n-butyllithium (2.5 M in hexane, 60 mL, 150.0 mmol) dropwise to 4-bromo-1-methoxy-2-methylbenzene (27.78 g, 138.2 mmol) at -78 °C solution in THF (300 mL). The mixture was stirred at -78°C for 1 hour and then added dropwise to a solution of ethyl 4-oxocyclohexanecarboxylate (22.34 g, 131.3 mmol) in THF (300 mL) at -78°C. The mixture was stirred at -78 °C for 2 h, added to saturated NH4 Cl (600 mL), and then extracted with EtOAc (2 x 600 mL). The combined organic extracts were washed with water (400 mL), washed with brine (400 mL), dried (Na2 SO4 ), filtered, concentrated, and purified by silica gel chromatography (petroleum ether/EtOAc=10/1) to give 4-hydroxy-4-(4-methoxy-3-methylphenyl as a yellow oil ) ethyl cyclohexanecarboxylate (18.9 g, 45%).1 H NMR (400 MHz, DMSO): δ 7.11-7.26 (m, 2H), 6.75-6.84 (m, 1H), 4.59-4.64 (m, 1H), 3.98-4.11 (m, 2H), 3.72 (s, 3H), 2.25-2.39 (m, 1H), 2.07-2.13 (s, 3H), 1.77-1.93 (m, 3H), 1.42-1.75 (m, 5H), 1.11-1.23 (m, 3H); LCMS: 275.2 [M-OH]+ .step 2 : 4 - Allyl - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Ethyl cyclohexanecarboxylate Boron trifluoride diethyl ether (24.85 g, 84.03 mmol) was added to ethyl 4-hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (18.90 g, 64.64 mmol) and allyltrimethylsilane (11.82 g, 103.42 mmol) in DCM (400 mL). The mixture was stirred at -78 °C for 1 h, at room temperature overnight, and then added to brine (200 mL) and DCM (200 mL). The organic layer was separated and washed with saturated NaHCO3 (2 × 200 mL), washed with brine (200 mL), dried (Na2 SO4 ), filtered, concentrated, and purified by silica gel chromatography (petroleum ether/EtOAc=20/1) to give 4-allyl-4-(4-methoxy-3-methyl as a yellow oil phenyl)cyclohexanecarboxylate (15 g, 71%).1 H NMR (400 MHz, CDCl3 ): δ 7.00-7.10 (m, 2H), 6.76 (d, 1H), 5.26-5.50 (m, 1H), 4.81-4.98 (m, 2H), 4.15 (q, 0.5H), 4.03 (q, 1.5 H), 3.81 (s, 3H), 2.26-2.42 (m, 3H), 2.21 (s, 3H), 2.15 (d, 1.5H), 1.98 (d, 0.5H), 1.75-1.88 (m, 2.5H ), 1.60-1.72 (m, 0.5H), 1.33-1.55 (m, 3H), 1.27 (t, 0.8H), 1.18 (t, 2.2H); LCMS: 339.3 [M+Na]+ .step 3 : 4 -( 2 , 3 - Dihydroxypropyl )- 4 -( 4 - Methoxy - 3 - methyl phenyl ) Ethyl cyclohexanecarboxylate Osmium tetroxide (0.1 M in tert-butanol, 7.6 mL, 0.76 mmol) was added to 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexyl at 0 °C Ethyl alkanoate (4.81 g, 15.2 mmol), 4-methylmorpholineN -oxide (2.67 g, 22.8 mmol), CH3 CN (100 mL) and H2 O (25 mL) solution. The mixture was stirred overnight at room temperature. will saturate Na2 SO3 (50 mL) was added to the mixture. The mixture was stirred at room temperature for 30 min, concentrated, dissolved in water (80 mL) and extracted with EtOAc (2 x 100 mL). dry (Na2 SO4 ) organic layer, filtered, concentrated, and purified by silica gel chromatography (petroleum ether/EtOAc=1/1) to give 4-(2,3-dihydroxypropyl)-4-(4 - ethyl methoxy-3-methylphenyl)cyclohexanecarboxylate (5.23 g, 94%).1 H NMR (400 MHz, CDCl3 ): δ 7.05-7.16 (m, 2H), 6.78 (d, 1H), 4.06-4.17 (m, 0.5H), 3.95-4.05 (m, 1.5H), 3.80 (s, 3H), 3.48-3.66 ( m, 1H), 3.18-3.32 (m, 2H), 2.40-2.53 (m, 2H), 2.27-2.37 (m, 1H), 2.19 (s, 3H), 1.80 (t, 3H), 1.32-1.68 ( m, 7H), 1.24-1.25 (m, 0.8H), 1.17 (t, 2.2H); LCMS: 373.3 [M+Na]+ .step 4 : 4 -( 4 - Methoxy - 3 - methyl phenyl )- 4 -( 2 - Pendant oxyethyl ) Ethyl cyclohexanecarboxylate Add sodium periodate (3.83 g, 17.90 mmol) to 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexane at 0 °C Ethyl formate (5.23 g, 14.9 mmol), THF (70 mL) and H2 O (35 mL) solution. The mixture was stirred overnight at room temperature and then added to water (50 mL) and EtOAc (2 x 100 mL). The organic layer was separated, washed with water (80 mL), washed with brine (80 mL), dried (Na2 SO4 ), filtered, concentrated and purified by silica gel chromatography (petroleum ether/EtOAc=5/1) to give 4-(4-methoxy-3-methylphenyl)-4-( Ethyl 2-oxoethyl)cyclohexanecarboxylate (3.95 g, 82%).1 H NMR (400 MHz, CDCl3 ): δ 9.28-9.42 (m, 1H), 7.07-7.19 (m, 2H), 6.79 (d, 1H), 4.15 (q, 0.5H), 4.04 (q, 1.5H), 3.82 (s, 3H) , 2.41-2.52 (m, 3H), 2.33 (s, 1H), 2.21 (s, 3H), 1.75-1.92 (m, 3H), 1.46-1.63 (m, 4H), 1.23-1.31 (t, 0.5H ), 1.19 (t, 2.5H); LCMS: 341.3 [M+Na]+ .step 5 : 4 -( 2 - Hydroxyethyl )- 4 -( 4 - Methoxy - 3 - methyl phenyl ) Ethyl cyclohexanecarboxylate Sodium borohydride (704 mg, 18.6 mmol) was added to ethyl 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanecarboxylate at 0 °C A solution of the ester (3.95 g, 12.41 mmol) in THF (100 mL). The mixture was stirred at 0 °C for 1 h, at room temperature overnight, and then diluted with water (100 mL). The organic solvent was removed under reduced pressure, and the aqueous layer was extracted with DCM (2 x 300 mL). dry (Na2 SO4 ) organic extract, filtered, concentrated, and purified by silica gel chromatography (petroleum ether:EtOAc=3:1) to give 4-(2-hydroxyethyl)-4-(4-methanol as a yellow oil Ethyl oxy-3-methylphenyl)cyclohexanecarboxylate (3.11 g, 67%).1 H NMR (400 MHz, CDCl3 ): δ 6.96-7.04 (m, 2H), 6.71 (d, 1H), 4.03-4.12 (q, 0.4H), 3.97 (q, , 1.6H), 3.74 (s, 3H), 3.28-3.38 (m , 2H), 2.19-2.39 (m, 3H), 2.14 (s, 3H), 1.71-1.80 (m, 2H), 1.60-1.70 (m, 2H), 1.28-1.50 (m, 4H), 1.17-1.24 (t, 1H), 1.12 (t, 2H), (OH proton not detected); LCMS: 343.2 [M+Na]+ .step 6 : 4 -( 2 - Bromoethyl )- 4 -( 4 - Methoxy - 3 - methyl phenyl ) Ethyl cyclohexanecarboxylate A solution of triphenylphosphine (4.60 g, 17.54 mmol) in DCM (20 mL) was added dropwise to 4-(2-hydroxyethyl)-4-(4-methoxy-3-methyl) at 0 °C Phenyl) ethyl cyclohexanecarboxylate (2.81 g, 8.77 mmol), CBr4 (4.36 g, 13.16 mmol) and DCM (40 mL). The mixture was stirred at 0 °C for 1 h, at room temperature overnight, concentrated, and then purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give 4-(2-bromo as a yellow oil Ethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (2.62 g, 77%).1 H NMR (400 MHz, CDCl3 ): δ 6.96-7.08 (m, 2H), 6.77 (d, 1H), 4.15 (q, 0.3H), 4.03 (q, 1.7H), 3.81 (s, 3H), 2.91-3.06 (m, 2H) , 2.24-2.41 (m, 3H), 2.15-2.24 (s, 3H), 1.95-2.06 (m, 2H), 1.77-1.87 (m, 2H), 1.34-1.53 (m, 4H), 1.27 (t, 1H), 1.18 (t, 2H); LCMS: 405.1 [M+Na]+ .step 7 : 4 -( 4 - Methoxy - 3 - methyl phenyl ) Shuanghuan [ 2 . 2 . 2 ] Octane - 1 - ethyl formate Lithium diisopropylamide (2M in THF, 4.8 mL, 9.60 mmol) was added dropwise to 4-(2-bromoethyl)-4-(4-methoxy-3-methyl In a solution of ethyl phenyl)cyclohexanecarboxylate (1.81 g, 4.72 mmol), HMPA (4.23 g, 23.61 mmol) and THF (90 mL). The mixture was stirred at -78 °C for 3 h, added to saturated NH4 Cl (90 mL), and then extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with water (100 mL), washed with brine (100 mL), dried (Na2 SO4 ), filtered, concentrated, and purified by silica gel chromatography (petroleum ether/EtOAc=30/1) to give 4-(4-methoxy-3-methylphenyl)bicyclo[2.2 .2] Octane-1-carboxylic acid ethyl ester (1.17 g, 82%).1 H NMR (400 MHz, CDCl3 ): δ 6.98-7.05 (m, 2H), 6.69 (d, 1H), 4.05 (q, 2H), 3.73 (s, 3H), 2.14 (s, 3H), 1.70-1.87 (m, 12H), 1.18 (t, 3H); LCMS: 303.3 [M+H]+ .step 8 : ( 4 -( 4 - Methoxy - 3 - methyl phenyl ) Shuanghuan [ 2 . 2 . 2 ] pungent - 1 - base ) Methanol Diisobutylaluminum hydride (1 M in toluene, 14 mL, 14.0 mmol) was added to 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane at -78 °C A solution of ethyl alkane-1-carboxylate (1.64 g, 5.42 mmol) in DCM (100 mL). The mixture was stirred at -78°C for 1 hour, at room temperature for 2 hours, and then added to ice water (80 mL). The mixture was adjusted to (pH = 6) with 1 N HCl and filtered. The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 200 mL). The combined organic layers were washed with water (100 mL), washed with brine (100 mL), dried (Na2 SO4 ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1) to afford (4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane as a yellow solid -1-yl)methanol (1.22 g, 82%).1 H NMR (400 MHz, CDCl3 ): δ 6.99-7.07 (m, 2H), 6.64-6.72 (m, 1H), 3.73 (s, 3H), 3.25 (s, 2H), 2.14 (s, 3H), 1.69-1.81 (m, 6H) , 1.40-1.50 (m, 6H); LCMS: 261.2 [M+H]+ .step 9 : 4 -( 4 - Methoxy - 3 - methyl phenyl ) Shuanghuan [ 2 . 2 . 2 ] Octane - 1 - formaldehyde Pyridinium chlorochromate (1.03 g, 4.78 mmol) was added to (4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]oct-1-yl)methanol (621.1 mg, 2.39 mmol), SiO2 (1.93 g, 32.19 mmol) and DCM (120 mL). The mixture was stirred at room temperature for 2 hours, filtered through a plug of neutral alumina and concentrated to give 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane- 1-Carboxaldehyde (601.3 mg, 93%).1 H NMR (400 MHz, CDCl3 ): δ 9.48-9.56 (s, 1H), 7.06-7.11 (m, 2H), 6.72-6.78 (m, 1H), 3.81 (s, 3H), 2.22 (s, 3H), 1.83-1.91 (m, 6H), 1.71-1.80 (m, 6H); LCMS: 259.3 [M+H]+ . follow forintermediate 3 The procedure described consists of 5-bromo-N ,N -Lutidine-2-amine The following intermediates were synthesized.
Figure AA12
 Alternate conditions: Step 2: 0 °C, overnight; Step 3: K2 OSo4 2H2 O; Step 7: -78 °C, 1 hour then room temperature, overnight; Step 9: Acetyl chloride, DMSO, Et3 N, -78°C.intermediate 4 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base ) aniline
Figure 02_image267
With vacuum/N2 Cycle (3×) to make 3-iodoaniline (63.36 g, 289.9 mmol), Pd(dppf)Cl2 (7.05 g, 9.63 mmol), K2 CO3 (2.2 M, 265 mL, 583.0 mmol) and dioxane (340 mL) was degassed. Add 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (about 90%, 50.09 g, 192.6 mmol), and the mixture was heated in a preheated oil bath (90° C.) for 20 minutes (internal temperature at 20 minutes was 72° C.). The reaction was cooled to room temperature, washed with EtOAc (800 mL) and H2 O (800 mL) was diluted, and then filtered through Celite while washing with EtOAc (ca. 400 mL). The layers were separated, and washed (800 mL H2 O) The organic layer was dried (Na2 SO4 ), filtered and concentrated (73.88 g). The dry residue was loaded onto silica gel and purified by silica gel chromatography (20% to 60% EtOAc/hexanes) to afford 3-(1-cyclopropyl-1H-pyrazole-4- base) aniline (31.5 g, 82%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.03 (s, 1H), 7.66 (d, 1H), 6.97 (t, 1H), 6.73-6.72 (m, 1H), 6.71-6.68 (m, 1H), 6.42-6.38 (m, 1H) , 5.00 (s, 2H), 3.75-3.68 (m, 1H), 1.08-1.00 (m, 2H), 1.00-0.92 (m, 2H); LCMS: 200.3 [M+H]+ . follow forintermediate 4 The procedure described consists of the appropriate aryl halide and the appropriate
Figure 107108918-A0304-12-0030-1
Acid/ester synthesis of the following intermediates.
Figure AA13
Figure AA14
 1 4-Bromopyridin-2-amine was used.2 4-Bromo-6-methylpyridin-2-amine was used.intermediate 5 3 -( 3 - methyl - 1 h - pyrazole - 1 - base ) aniline
Figure 02_image281
step 1 : 3 - methyl - 1 -( 3 - nitrobenzene )- 1H - pyrazole 1-fluoro-3-nitrobenzene (2.00 g, 14.17 mmol), 3-methyl-1h - pyrazole (2.33 g, 28.34 mmol), K2 CO3 (1.96 g, 14.17 mmol) and DMSO (20 mL) was heated to 120 °C overnight. The reaction mixture was filtered and filtered by RP-HPLC [water (10 mM NH4 HCO3 )-MeCN] to purify the filtrate to give 3-methyl-1-(3-nitrobenzene)-1 as pale yellow solidh - Pyrazole (2.0 g, 69%).1 H NMR (400 MHz, CDCl3 ): δ: 8.50 (t, 1H), 7.99-8.14 (m, 2H), 7.91 (d, 1H), 7.60 (t, 1H), 6.32 (d, 1H), 2.39 (s, 3H); LCMS: 203.9 [M+H]+ .step 2 :3 -( 3 - methyl - 1 h - pyrazole - 1 - base ) aniline in N2 Palladium/carbon (10 wt.%, 50 mg, 0.047 mmol) was added to 3-methyl-1-(3-nitrobenzene)-1 underh - A solution of pyrazole (1.0 g, 4.92 mmol) in MeOH (5 mL). With 3 vacuum/H2 cycle to degas the mixture at room temperature under H2 (15 psi) for 2 hours, filtered, and concentrated under high vacuum to give 3-(3-methyl-1h -pyrazol-1-yl)aniline (400 mg, crude material).1 H NMR (400 MHz, CDCl3 ): δ: 7.77 (d, 1H), 7.18 (t, 1H), 7.07 (t, 1H), 6.95 (dd, 1H), 6.56 (dd, 1H), 6.22 (d, 1H), 3.81 (s, 2H), 2.37 (s, 3H); LCMS: 174.1 [M+H]+ .intermediate 6 3 - iodine - N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl ) aniline
Figure 02_image283
at room temperature in N2 Sodium triacetoxyborohydride (3.74 g, 17.6 mmol) was added tointermediate 1 (2.56 g, 11.0 mmol), 3-iodoaniline (2.56 g, 11.7 mmol), acetic acid (1.3 mL, 23 mmol) and dichloroethane (45 mL). The reaction was stirred for 80 min and poured into 50 mL of saturated NaHCO3 and extracted with 50 mL EtOAc. Sat. NaHCO with 50 mL3 The EtOAc layer was washed and washed with 50 mL of brine. The aqueous layers were combined and back extracted with 25 mL EtOAc. dry (Na2 SO4 ) combined organics, filtered, concentrated and purified by silica gel chromatography (0% to 5% EtOAc/hexanes) to give 3-iodo-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)aniline (4.43 g, 88%).1 H NMR (400 MHz, DMSO-d 6 ): δ 7.01-6.95 (m, 2H), 6.91 (s, 1H), 6.86-6.77 (m, 3H), 6.57 (d, 1H), 5.92 (t, 1H), 3.73 (s, 3H), 2.85 (t, 2H), 2.42-2.31 (m, 1H), 2.11 (s, 3H), 1.94-1.85 (m, 2H), 1.82-1.73 (m, 2H), 1.63-1.50 (m, 1H), 1.45 -1.31 (m, 2H), 1.14-1.00 (m, 2H); LCMS: 436.4 [M+H]+ .intermediate 7 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base )- N -(( 4 -( 4 - Methoxy - 3 - methyl phenyl ) Shuanghuan [ 2 . 2 . 2 ] pungent - 1 - base ) methyl ) aniline
Figure 02_image285
in N2 Cool the dichloroethane in an ice/water bath. At 0°C theintermediate 3 (151 mg, 0.58 mmol),intermediate 4 (118 mg, 0.59 mmol), and then sodium triacetyloxyborohydride (198 mg, 0.93 mmol) was added to the reaction. The reaction was warmed to room temperature, stirred at room temperature for 85 min, and poured into 20 mL of saturated NaHCO3 , and then extracted with 20 mL EtOAc. The organic layer was washed with 20 mL of brine, dried (Na2 SO4 ), filtered, concentrated and purified by silica gel chromatography (10% to 30% EtOAc/hexanes) to give 3-(1-cyclopropyl-1h -pyrazol-4-yl)-N -((4-(4-Methoxy-3-methylphenyl)bicyclo[2.2.2]oct-1-yl)methyl)aniline (233 mg, 90%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.09 (s, 1H), 7.71 (s, 1H), 7.11-7.05 (m, 2H), 7.00 (t, 1H), 6.84-6.76 (m, 2H), 6.68 (d, 1H), 6.47 (d, 1H), 5.32 (t, 1H), 3.75-3.68 (m, 4H), 2.83 (d, 2H), 2.12 (s, 3H), 1.78-1.69 (m, 6H), 1.62-1.52 (m , 6H), 1.10-1.04 (m, 2H), 1.00-0.93 (m, 2H); LCMS: 442.3 [M+H]+ . follow forintermediate 6 andintermediate 7 The described procedure synthesizes the following intermediates from appropriate amines (SM or intermediates) and appropriate aldehyde intermediates.
Figure AA15
Figure AA16
Figure AA17
Figure AA18
Figure AA19
 1 Substitution condition: NaBH3 CN, AcOH, MeOH, room temperature, overnight;2 The solvent is DCM.intermediate 8 opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen ) Cyclohexaneformyl chloride
Figure 02_image361
step 1 :07:51 PM 2018/12/9 opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen ) tertiary butyldimethylsilyl cyclohexanecarboxylate at room temperature in N2 tert-Butyldimethylchlorosilane (31.47 g, 208.8 mmol) was added to trans-4-hydroxy-cyclohexanecarboxylic acid (10.03 g, 69.57 mmol), imidazole (18.96 g, 278.5 mmol) and DMF (140 mL) (the reaction exothermed to 32 °C). The reaction was stirred at room temperature for 2 hours, and then diluted with 300 mL of ether. The organic layer was washed with 1 N HCl (2 × 300 mL), washed with 300 mL brine, and dried (Na2 SO4 ), filtered and concentrated to give tert-butyldimethylsilyl trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (31.5 g) as a clear oil.1 H NMR (400 MHz, DMSO-d 6 ): δ 3.61-3.53 (m, 1H), 2.26-2.18 (m, 1H), 2.04-1.96 (m, 2H), 1.92-1.85 (m, 2H), 1.51-1.39 (m, 2H), 1.39- 1.27 (m, 2H), 0.94 (s, 9H), 0.89 (s, 9H), 0.26 (s, 6H), 0.06 (s, 6H).step 2 : opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen ) Cyclohexanecarboxylic acid at room temperature in N2 An aqueous solution (300 mL) of potassium carbonate (58.01 g, 419.7 mmol) was added to trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid tert-butyldimethylsilane In a mixture of ester (31.5 g crude material, 69.6 mmol), ethanol (1000 mL) and THF (300 mL). The reaction was stirred at room temperature for 3 hours, concentrated until 300 mL remained, diluted with 600 mL of brine, and then washed with 20% NaHSO4 (550 mL) acidified to pH 2 to pH 3. The aqueous layer was extracted with 800 mL of ether. The organic layer was washed with 800 mL brine, dried (Na2 SO4 ), filtered and concentrated to afford trans-4-((t-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid (17.3 g, 96% over 2 steps) as a white solid.1 H NMR (400 MHz, DMSO-d 6 ): δ 12.30 (br s, 1H), 3.59-3.51 (m, 1H), 2.15-2.05 (m, 1H), 1.88-1.74 (m, 4H), 1.41-1.29 (m, 2H), 1.28-1.16 (m, 2H), 0.84 (s, 9H), 0.02 (s, 6H).step 3 : opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen ) Cyclohexaneformyl chloride (Chloromethylene)dimethylimmonium chloride (34.02 g, 265.78 mmol) was weighed into a 1000 mL round bottom flask (3 neck) and vacuum/N2 Cycle (3x) to degas. Toluene (240 mL) was added to the flask, and the mixture was cooled (1.3 °C) in an ice bath. Anhydrous potassium carbonate* (68.71 g, 497.14 mmol) and trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid (34.29 g, 132.69 mmol) were sequentially added to the reaction. The ice bath was removed, and the mixture was stirred for 35 minutes. Celite (7 g) was added to the reaction, and the reaction was then filtered through Celite (70 g, Chemglass 465 mL sintered funnel) and washed with toluene (3 x 100 mL). This solution (451 g, 8.5% acid chloride, 100% yield, 72 mg/mL) was used directly in the acylation reaction.1 H NMR (400 MHz, CDCl3 ): δ 3.77-3.68 (m, 1H), 2.83-2.74 (m, 1H), 2.31-2.22 (m, 2H), 2.09-1.99 (m, 2H), 1.76-1.63 (m, 2H), 1.54- 1.42 (m, 2H), 1.02 (s, 9H), 0.20 (s, 6H). *Potassium carbonate was dried under vacuum by heating with an air heat gun for about 5 minutes, and then allowed to cool overnight. follow forintermediate 8 The described procedure synthesized the following intermediates from appropriate starting materials.
Figure AA20
 1 Step 3 only.2 Step 1: Ethyl 4-oxocyclohexanecarboxylate, AlMe3 , toluene, 0° C., 1 hour, yields ethyl 4-hydroxy-4-methylcyclohexanecarboxylate as a cis/trans mixture; step 2: TBSOTf, 2,6-lutidine, DCM, 0 °C to room temperature, overnight; Step 3: LiOH·H2 O, H2 O, THF; Step 4: Step 3 for Intermediate 8.intermediate 9 opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen )- N -( 3 - iodophenyl )- N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl ) Cyclohexaneformamide
Figure 02_image371
Willintermediate 8 (74 mg/mL in toluene, 43 mL, 11.49 mmol) was added tointermediate 6 (3.32 g, 7.63 mmol), pyridine (2.5 mL, 31 mmol) and toluene (15 mL). The mixture was stirred at room temperature for 90 min, diluted with EtOAc (50 mL), and washed (50 mL H2 O, 50 mL saturated NaHCO3 , and then 50 mL of saline). dry (Na2 SO4 ) organic layer, filtered, concentrated, and purified by silica gel chromatography (0% to 10% EtOAc/hexanes) to afford trans-4-((tert-butyldimethylsilyl) as a white foam Oxygen)-N -(3-iodophenyl)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (4.05 g, 79%).1 H NMR (400 MHz, DMSO-d 6 ): δ 7.76 (d, 1H), 7.72 (s, 1H), 7.31 (d, 1H), 7.27 (t, 1H), 6.97-6.92 (m, 2H), 6.80-6.76 (m, 1H), 3.72 (s, 3H), 3.60-3.40 (m, 3H), 2.37-2.27 (m, 1H), 2.09 (s, 3H), 2.01-1.91 (m, 1H), 1.78-1.67 (m, 6H), 1.65 -1.56 (m, 2H), 1.49-1.21 (m, 5H), 1.10-0.94 (m, 2H), 0.92-0.76 (m, 11H), -0.01 (s, 6H); LCMS: 676.6 [M+H ]+ . follow forintermediate 9 The described procedure synthesized the following intermediates from the appropriate intermediates.
Figure AA21
 1 Alternative conditions used: TEA, DCM, room temperature, overnight.intermediate 10 opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen )- N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl )- N -( 3 -( 4 , 4 , 5 , 5 - Tetramethyl - 1 , 3 , 2 - Boron dioxide - 2 - base ) Phenyl ) Cyclohexaneformamide
Figure 02_image379
Use 3 times of vacuum/N2 Cycle bis(pinacolate)diboron (1.42 g, 5.59 mmol), potassium acetate (1.45 g, 14.8 mmol), Pd(dppf)Cl2 (135 mg, 0.18 mmol) and toluene (23 mL) was degassed. Willintermediate 9 (2.50 g, 3.70 mmol) was added to the mixture and vacuum/N2 The reaction was cycled to degas, heated at 115 °C for 3.5 hours, and then allowed to cool to room temperature. The mixture was diluted with 75 mL EtOAc. with saturated NaHCO3 (2 × 75 mL) washed organics, dried (Na2 SO4 ), filtered, concentrated, and dried overnight under high vacuum to obtain trans-4-((tert-butyldimethylsilyl)oxy)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N -(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)cyclohexanecarboxamide (2.99 g, 120% crude product) .1 H NMR (400 MHz, CDCl3 ): δ 7.82-7.78 (m, 1H), 7.61-7.57 (m, 1H), 7.43 (t, 1H), 7.27-7.24 (m, 1H), 6.99-6.94 (m, 2H), 6.74 (d, 1H), 3.80 (s, 3H), 3.72-3.45 (m, 3H), 2.44-2.33 (m, 1H), 2.20 (s, 3H), 2.11-2.01 (m, 1H), 1.90-1.76 (m, 6H), 1.75-1.65 (m, 3H), 1.58-1.47 (m, 2H), 1.42-1.32 (m, 14H), 1.24-1.10 (m, 2H), 1.06-0.92 (m, 2H), 0.84 ( s, 9H), 0.01 (s, 6H); LCMS: 676.6 [M+H]+ . Note:intermediate 10 also byintermediate 9 Synthesized in the bromide form.intermediate 11 opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen )- N -( 3 - Ethynylphenyl )- N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl ) Cyclohexaneformamide
Figure 02_image381
step 1 : opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen )- N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl )- N -( 3 -(( Trimethylsilyl ) Ethynyl ) Phenyl ) Cyclohexaneformamide in N2 Ethynyl (trimethyl) silane (7.56 g, 76.95 mmol, 10.65 mL), CuI (733 mg, 3.85 mmol) and Pd(PPh3 )2 Cl2 (2.70 g, 3.85 mmol) added tointermediate 9 (26 g, 38.48 mmol) in Et3 solution in N (260 mL). The mixture was stirred at 90 °C for 6 hours, cooled to room temperature, and then diluted with ethyl acetate (250 mL). with 250 mL H2 O wash mixture. dry (Na2 SO4 ) organic layer, filtered, and concentrated. The crude material was purified by silica gel chromatography (petroleum ether/ethyl acetate = 20:1 to 5:1) to afford trans-4-((t-butyldimethylsilyl)oxyl as a yellow oil )-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N -(3-((Trimethylsilyl)ethynyl)phenyl)cyclohexanecarboxamide (21.5 g, 78% yield).1 H NMR (400 MHz, CDCl3 ): δ 7.45-7.47 (m, 1H), 7.34-7.38 (m, 1H), 7.26-7.27 (m, 1H), 7.12-7.14 (m, 1H), 6.95-6.97 (m, 2H), 6.73- 6.75 (m, 1H), 3.80 (s, 3H), 3.50-3.58 (m, 3H), 2.35-2.38 (m, 1H), 2.19 (s, 3H), 1.84-1.88 (m, 1H), 1.77- 1.84 (m, 6H), 1.56-1.66 (m, 4H), 1.34-1.37 (m, 3H), 1.13-1.16 (m, 2H), 1.00-1.04 (m, 2H), 0.84 (s, 9H), 0.29 (s, 9H), 0.01 (s, 6H); LCMS: 646.5 [M+H]+ .step 2 : opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen )- N -( 3 - Ethynylphenyl )- N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl ) Cyclohexaneformamide Ammonium fluoride (2.87 g, 77.39 mmol) was added to trans-4-((tert-butyldimethylsilyl)oxy)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N - A solution of (3-((trimethylsilyl)ethynyl)phenyl)cyclohexanecarboxamide (10 g, 15.48 mmol) in MeOH (100 mL). The mixture was stirred at 60 °C for 1 h, and then concentrated. The crude material was purified by silica gel chromatography (petroleum ether/ethyl acetate = 100/1 to 10:1) to afford trans-4-((t-butyldimethylsilyl)oxyl as a yellow oil )-N -(3-Ethynylphenyl)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (7.8 g, 88% yield).1 H NMR (400 MHz, CDCl3 ): δ 7.49-7.51 (m, 1H), 7.40-7.42 (m, 1H), 7.31 (s, 1H), 7.17-7.19 (m, 1H), 6.95-6.97 (m, 2H), 6.73-6.75 ( m, 1H),3.80 (s, 3H), 3.50-3.60 (m, 3H), 3.17 (s, 1H), 2.38-2.41 (m, 1H), 2.20 (s, 3H), 1.86-1.89 (m, 1H), 1.77-1.85 (m, 6H), 1.61-1.66 (m, 4H), 1.34-1.37 (m, 3H), 1.14-1.17 (m, 2H), 1.00-1.04 (m, 2H), 0.84 ( s, 9H), 0.01 (s, 6H).intermediate 12 ; for intermediates 1 . 04 Of SM 6- chlorine - 3 - Methoxy - 2 - Cyanopyridine
Figure 02_image383
step 1 : 2 - cyano - 3 - Methoxypyridine 1 - Oxide 3- Chloroperbenzoic acid (90.8 g, 447 mmol, 85% purity) was added to 3-methoxy-2-cyanopyridine (50 g, 373 mmol) in DCE (500 mL) at room temperature in solution. The reaction mixture was heated at 65 °C overnight and then allowed to cool to room temperature. with NaHCO3 (5 × 300 mL) washed the mixture, washed with Na2 SO4 Drying, filtration, concentration, and subsequent trituration in petroleum ether/EtOAc = 5/1 (300 mL) afforded 2-cyano-3-methoxypyridine 1-oxide (50 g, 89%).1 H NMR (400MHz, CDCl3 ): δ 7.95 (d, 1H), 7.37 (t, 1H), 6.90 (d, 1H), 4.03 (s, 3H); LCMS: 151.0 [M+H]+ .step 2 : 6 - chlorine - 3 - Methoxy - 2 - Cyanopyridine in N2 2-cyano-3-methoxypyridine 1-oxide (30 g, 200 mmol) and POCl3 (333 g, 2.17 mol) mixture was heated to 100°C for 2 hours. The mixture was concentrated to dryness and washed with NaHCO3 (300 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2 SO4 ), filtered, concentrated, and subsequently purified by silica gel chromatography (petroleum ether/EtOAc=2/1) to give 6-chloro-3-methoxy-2-cyanopyridine (20 g , 59%).1 H NMR (400MHz, CDCl3 ): δ 7.51 (d, 1H), 7.38 (d, 1H), 3.99 (s, 3H); LCMS: 169.0 [M+H]+ .intermediate 13 ; for intermediates 1 . 09 Of SM 5- bromine - 1 - methyl - 1 h - pyrrolo [ 2 , 3 - c ] pyridine
Figure 02_image385
at 0°C in N2 Sodium hydride (3.65 g, 91.36 mmol, 60% purity) was added to 5-bromo-1h - A solution of pyrrolo[2,3-c]pyridine (9 g, 45.68 mmol) in DMF (100 mL). The reaction was stirred for 0.5 h, and then at 0 °C under N2 Add Me drop by drop2 SO4 (5.76 g, 45.68 mmol). The reaction was warmed to room temperature for 2 hours, poured into water (200 mL), and extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with water (2 × 100 mL), washed with brine (100 mL), washed with Na2 SO4 Drying, filtration, concentration, and subsequent purification by silica gel chromatography (petroleum ether/EtOAc=4/1) gave 5-bromo-1-methyl-1 as a yellow solidh - Pyrrolo[2,3-c]pyridine (9.6 g, 99.5%).1 H NMR (400MHz, DMSO-d 6 ): δ 8.64 (s, 1H), 7.73 (s, 1H), 7.63 (d, 1H), 6.47 (d, 1H), 3.89 (s, 3H); LCMS: 211.0 [M+H]+ .intermediate 14 ; for intermediates 1 . 03 Of SM 5- bromine - 3 - fluorine - 1 - methyl - 1 h - Indazole
Figure 02_image387
1-(Chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diumium tetrafluoroborate (16.11 g, 45.48 mmol) was added to 5-Bromo-1-methyl-1h -Indazole (8.00 g, 37.90 mmol) in CH3 CN (80 mL). The mixture was stirred overnight at 80 °C and washed with H at room temperature2 O (50 mL) was quenched and then diluted with EtOAc (50 mL). The mixture was extracted with EtOAc (3 x 50 mL). by Na2 SO4 The combined organic layers were dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 50 to 5:1) to give 5-bromo-3-fluoro-1-methyl-1 as a white solidh - Indazole (3.95 g, 46%).1 H NMR (400 MHz, DMSO-d 6 ): δ 7.93 (s, 1H), 7.53-7.65 (m, 2H), 3.90 (s, 3H).compound 1 opposite - 4 - hydroxyl - N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl )- N -( 3 -( 4 - methyl - 1 h - pyrazole - 1 - base ) Phenyl ) Cyclohexaneformamide
Figure 02_image389
step 1 : opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen )- N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl )- N -( 3 -( 4 - methyl - 1 h - pyrazole - 1 - base ) Phenyl ) Cyclohexaneformamide Will Cu2 O (2.6 mg, 0.019 mmol), Cs2 CO3 (241 mg, 0.740 mmol), salicylaldoxime (10 mg, 0.074 mmol) and 4-methyl-1h - Pyrazole (45.5 mg, 0.555 mmol) was added tointermediate 9 (250 mg, 0.370 mmol) in CH3 CN (10 mL). at 80°C in N2 The resulting mixture was stirred overnight, allowed to cool to room temperature, filtered and concentrated in vacuo. The crude product was purified by preparative TLC (PE/EA = 10/1) to give trans-4-((t-butyldimethylsilyl)oxy)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N -(3-(4-Methyl-1h -pyrazol-1-yl)phenyl)cyclohexanecarboxamide (100 mg, 43%). LCMS: 630.5 [M+H]+ .step 2 : opposite - 4 - hydroxyl - N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl )- N -( 3 -( 4 - methyl - 1 h - pyrazole - 1 - base ) Phenyl ) Cyclohexaneformamide Aqueous hydrochloric acid (1 M, 0.5 mL) was added to trans-4-((tert-butyldimethylsilyl)oxy)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N -(3-(4-Methyl-1h -pyrazol-1-yl)phenyl)cyclohexanecarboxamide (80.0 mg, 0.127 mmol) in MeOH (4 mL). The mixture was stirred at room temperature for 0.5 h, poured into 10 mL of cold water, and then extracted with 5% MeOH/DCM (15 mL). The organic layer was washed with 10 mL of brine, dried (Na2 SO4 ), filtered, concentrated, and purified by prep-TLC (PE/EA=1/1) to give trans-4-hydroxy-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N -(3-(4-Methyl-1h -pyrazol-1-yl)phenyl)cyclohexanecarboxamide (21 mg, 32%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.37 (s, 1H), 7.77-7.86 (m, 1H), 7.73 (s, 1H), 7.52-7.62 (m, 2H), 7.20 (d, 1H), 6.92-6.96 (m, 2H) , 6.78 (d, 1H), 4.35-4.42 (m, 1H), 3.72 (s, 3H), 3.54-3.61 (m, 2H), 3.26-3.30 (m, 1H), 2.00-2.12 (m, 7H ), 1.69-1.80 (m, 6H), 1.59-1.68 (m, 2H), 1.22-1.49 (m, 6H), 0.99-1.12 (m, 2H), 0.70-0.85 (m, 2H); LCMS: 516.2 [M+H]+ .compound 2 opposite - N -(( opposite - 4 -( 3 - cyano - 4 - Methoxyphenyl ) Cyclohexyl ) methyl )- N -( 3 -( 1 - Ethyl - 1 h - pyrazole - 4 - base ) Phenyl )- 4 - Hydroxycyclohexanecarboxamide
Figure 02_image391
step 1 : opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen )- N -(( opposite - 4 -( 3 - cyano - 4 - Methoxyphenyl ) Cyclohexyl ) methyl )- N -( 3 -( 1 - Ethyl - 1 h - pyrazole - 4 - base ) Phenyl ) Cyclohexaneformamide Use 3 times of vacuum/N2 cycleintermediate 9 . 01 (101 mg, 0.15 mmol), (1-ethyl-1h -pyrazol-4-yl)
Figure 107108918-A0304-12-0030-1
acid (33 mg, 0.24 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), dioxane (1.5 mL) and 0.4 M K2 CO3 (1.1 mL, 0.44 mmol) was degassed, stirred at 80°C for 25 minutes, allowed to cool to room temperature, and poured into 20 mL of saturated NaHCO3 , and then extracted with 20 mL EtOAc. The organic matter was washed with 20 mL of brine, dried (Na2 SO4 ), filtered, concentrated, and purified by silica gel chromatography (20% to 50% ethyl acetate in hexane) to give trans-4-((tert-butyldimethylsilyl)oxy)-N -((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)-N -(3-(1-Ethyl-1h -pyrazol-4-yl)phenyl)cyclohexanecarboxamide (79 mg, 81%). LCMS: 655.5 [M+H]+ .step 2 : opposite - N -(( opposite - 4 -( 3 - cyano - 4 - Methoxyphenyl ) Cyclohexyl ) methyl )- N -( 3 -( 1 - Ethyl - 1 h - pyrazole - 4 - base ) Phenyl )- 4 - Hydroxycyclohexanecarboxamide Aqueous hydrochloric acid (1 N, 0.17 mL, 0.17 mmol) was added to trans-4-((tert-butyldimethylsilyl)oxy)-N -((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)-N -(3-(1-Ethyl-1h -pyrazol-4-yl)phenyl)cyclohexanecarboxamide (79 mg, 0.12 mmol), methanol (0.5 mL) and tetrahydrofuran (0.5 mL). The reaction was warmed to room temperature, stirred at room temperature for 1 h, poured into 20 mL of low temperature saturated NaHCO3 , and then extracted with 20 mL EtOAc. Saturated with 20 mL NaHCO3 The organics were washed and washed with 20 mL of brine. The combined aqueous layers were back extracted with 20 mL EtOAc. dry (Na2 SO4 ) combined extracts, filtered, concentrated, and purified by silica gel chromatography (0% to 7% methanol in DCM) to give trans-N -((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)-N -(3-(1-Ethyl-1h -pyrazol-4-yl)phenyl)-4-hydroxycyclohexylcarboxamide (60 mg, 92%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.29 (s, 1H), 7.94 (s, 1H), 7.59 (d, 1H), 7.56-7.48 (m, 3H), 7.45 (t, 1H), 7.15-7.06 (m, 2H), 4.39 (d, 1H), 4.15 (q, 2H), 3.86 (s, 3H), 3.66-3.46 (m, 2H), 3.32-3.20 (m, 1H), 2.49-2.40 (m, 1H), 2.11-2.00 (m, 1H), 1.81-1.68 (m, 6H), 1.68-1.59 (m, 2H), 1.48-1.27 (m, 8H), 1.12-0.99 (m, 2H), 0.82-0.68 (m, 2H) ;LCMS: 541.4 [M+H]+ . follow forcompound 2 The procedure described is composed of suitable intermediates and suitable
Figure 107108918-A0304-12-0030-1
sour or
Figure 107108918-A0304-12-0030-1
esters to synthesize the following compounds.
Figure AA22
Figure AA23
 Alternative Conditions: Step 1:1 1 M Na2 CO3 , DMF, 50°C,2 Cs2 CO3 , DMF (1% to 2% water), 50°C,3 Pd(PPh3 )4 、Cs2 CO3 , DMF (2% water), 50°C; step 2:4 6 N HCl.compound 3 opposite - N -( 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- 4 - hydroxyl - N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl ) Cyclohexaneformamide
Figure 02_image411
step 1 : opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen )- N -( 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl ) Cyclohexaneformamide Use 3 times of vacuum/N2 Cycle 4-bromo-1-cyclopropyl-1h - pyrazole (65 mg, 0.35 mmol),intermediate 10 (163 mg, 0.20 mmol), Cs2 CO3 (196 mg, 0.60 mmol), Pd(dppf)Cl2 , DMF (2 mL) and H2 The mixture was degassed with O (20 µL), heated at 80 °C for 110 min, and allowed to cool to room temperature. Pour the reaction into 20 mL saturated NaHCO3 , and then extracted with EtOAc (2 x 20 mL). The combined organics were washed with 20 mL of brine, dried (Na2 SO4 ), filtered, concentrated, and purified by silica gel chromatography (10% to 30% ethyl acetate in hexane) to give trans-4-((tert-butyldimethylsilyl) as a white foam )oxy)-N -(3-(1-Cyclopropyl-1h -pyrazol-4-yl)phenyl)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (63 mg, 48%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 7.93 (s, 1H), 7.61 (d, 1H), 7.56-7.52 (m, 1H), 7.43 (t, 1H), 7.08 (d, 1H), 6.98-6.91 (m, 2H), 6.81-6.75 (m, 1H), 3.77-3.69 (m, 4H), 3.64-3.45 (m, 3H), 2.38-2.28 (m, 1H), 2.13-2.02 (m, 4H) , 1.81-1.68 (m, 6H), 1.68-1.59 (m, 2H), 1.51-1.36 (m, 3H), 1.36-1.22 (m, 2H), 1.12-0.95 (m, 6H), 0.89-0.74 ( m, 11H), -0.03 (s, 6H); LCMS: 656.6 [M+H]+ .step 2 : opposite - N -( 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- 4 - hydroxyl - N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl ) Cyclohexaneformamide Aqueous hydrochloric acid (6 N, 0.13 mL, 0.78 mmol) was added to trans-4-((tert-butyldimethylsilyl)oxy)-N -(3-(1-Cyclopropyl-1h -pyrazol-4-yl)phenyl)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (62 mg, 0.095 mmol), methanol (0.5 mL) and tetrahydrofuran (0.5 mL) of the solution. The reaction was warmed to room temperature, stirred for 40 min, and poured into 20 mL of low temperature saturated NaHCO3 , and then extracted with EtOAc. Saturated with 20 mL NaHCO3 The organics were washed and washed with 20 mL of brine. The first aqueous wash was back extracted with 20 mL of EtOAc. dry (Na2 SO4 ) combined extracts, filtered, concentrated, and purified by silica gel chromatography (0% to 7% MeOH/DCM) to afford trans-N -(3-(1-Cyclopropyl-1h -pyrazol-4-yl)phenyl)-4-hydroxyl-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (50 mg, 98%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.56-7.51 (m, 1H), 7.44 (t, 1H), 7.09 (d, 1H), 6.98-6.92 (m, 2H), 6.81-6.75 (m, 1H), 4.39 (d, 1H), 3.78-3.69 (m, 4H), 3.63-3.48 (m, 2H), 3.30-3.20 (m, 1H), 2.38 -2.28 (m, 1H), 2.09 (s, 3H), 2.08-1.99 (m, 1H), 1.80-1.68 (m, 6H), 1.67-1.58 (m, 2H), 1.48-1.37 (m, 3H) , 1.32-1.20 (m, 2H), 1.11-0.95 (m, 6H), 0.81-0.67 (m, 2H); LCMS: 542.5 [M+H]+ . follow forcompound 3 The procedure described is provided byintermediate 10 and the appropriate aryl halides to synthesize the following compounds.
Figure AA24
Figure AA25
 Alternative Conditions: Step 1:1 K2 CO3 Aqueous solution, dioxane, 80°C, 0.5 to 5 hours; step 2:2 1N HCl.compound 4 opposite - 4 - hydroxyl - N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl )- N -( 3 -(( 1 - methyl - 1 h - pyrazole - 4 - base ) Ethynyl ) Phenyl ) Cyclohexaneformamide
Figure 02_image439
step 1 : opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen )- N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl )- N -( 3 -(( 1 - methyl - 1 h - pyrazole - 4 - base ) Ethynyl ) Phenyl ) Cyclohexaneformamide at 80°C in N2 under stirringintermediate 11 (301 mg, 0.525 mmol), 4-iodo-1-methyl-1h -Pyrazole (131 mg, 0.629 mmol), CuI (10 mg, 0.053 mmol), Pd(PPh3 )2 Cl2 (37 mg, 0.052 mmol) and Et3 The mixture in N (5 mL) for 1 h, cooled to room temperature, poured into water (30 mL), and then extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried (Na2 SO4 ), filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (petroleum ether/ethyl acetate = 25:1 to 5:1) afforded trans-4-((t-butyldimethylsilyl)oxyl as a yellow oil )-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N -(3-((1-Methyl-1h -pyrazol-4-yl)ethynyl)phenyl)cyclohexanecarboxamide (115 mg, 29%).1 H NMR (400 MHz, CDCl3 ): δ 7.69 (s, 1H), 7.61 (s, 1H), 7.36-7.50 (m, 2H), 7.28-7.33 (m, 1H), 7.12 (d, 1H), 6.91-7.02 (m, 2H) , 6.75 (d, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 3.48-3.65 (m, 3H), 2.35-2.43 (m, 1H), 2.20 (s, 3H), 2.05-2.14 (m, 1H), 1.77-1.90 (m, 8H), 1.49-1.73 (m, 8H), 1.25-1.42 (m, 3H), 1.11-1.22 (m, 2H), 0.97-1.09 (m, 2H) , 0.81-0.89 (m, 9H); LCMS: 654.3 [M+H]+ .step 2 : opposite - 4 - hydroxyl - N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl )- N -( 3 -(( 1 - methyl - 1 h - pyrazole - 4 - base ) Ethynyl ) Phenyl ) Cyclohexaneformamide Aqueous hydrochloric acid (1 M, 0.30 mL) was added to trans-4-((tert-butyldimethylsilyl)oxy)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N -(3-((1-Methyl-1h -pyrazol-4-yl)ethynyl)phenyl)cyclohexanecarboxamide (111 mg, 0.170 mmol), MeOH (2 mL) and THF (2 mL). The ice/water bath was removed and the reaction was allowed to warm to room temperature. The mixture was stirred at room temperature for 1 h and poured into saturated NaHCO3 (40 mL), extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried (Na2 SO4 ), filtered and concentrated under reduced pressure. By RP-HPLC [water (10 mM NH4 HCO3 )-MeCN] to obtain trans-4-hydroxy-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N -(3-((1-Methyl-1h -pyrazol-4-yl)ethynyl)phenyl)cyclohexanecarboxamide (47.8 mg, 52%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.09 (s, 1H), 7.71 (s, 1H), 7.48-7.52 (m, 2H), 7.42 (s, 1H), 7.32 (s, 1H), 6.93-6.95 (m, 2H), 6.72 -6.83 (m, 1H), 4.34-4.47 (m, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 3.51-3.61 (m, 2H), 3.30-3.32 (m, 1H), 2.24 -2.38 (m, 1H), 2.09 (s, 3H), 1.90-2.01 (m, 1H), 1.67-1.79 (m, 6H), 1.55-1.67 (m, 2H), 1.21-1.49 (m, 5H) , 0.97-1.12 (m, 2H), 0.70-0.84 (m, 2H); LCMS: 540.3 [M+H]+ . follow forcompound 4 The procedure described is provided byintermediate 11 and appropriate halides to synthesize the following compounds.
Figure AA26
 compound 5 opposite - N -( 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- N -(( opposite - 4 -( 3 - fluorine - 1 - methyl - 1 h - Indazole - 5 - base ) Cyclohexyl ) methyl )- 4 - Hydroxycyclohexanecarboxamide
Figure 02_image447
step 1 : opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen )- N -( 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- N -(( opposite - 4 -( 3 - fluorine - 1 - methyl - 1 h - Indazole - 5 - base ) Cyclohexyl ) methyl ) Cyclohexaneformamide Willintermediate 8 (75 mg/mL toluene solution, 1.7 mL, 0.461 mmol) added to the water bath at room temperatureintermediate 7 . 06 (130 mg, 0.293 mmol), pyridine (95 µL, 1.17 mmol) and toluene (2.5 mL). The mixture was stirred at room temperature for 2 hours, diluted with EtOAc (20 mL), washed (20 mL of saturated NaHCO3 , and then 20 mL of brine), dried (Na2 SO4 ), filtered and concentrated. The residue was purified by silica gel chromatography (0% to 40% EtOAc/hexanes) to afford trans-4-((t-butyldimethylsilyl)oxy)- as a white foamN -(3-(1-Cyclopropyl-1h -pyrazol-4-yl)phenyl)-N -((trans-4-(3-fluoro-1-methyl-1h -indazol-5-yl)cyclohexyl)methyl)cyclohexanecarboxamide (184 mg, 90%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.54 (s, 1H), 7.50 (dd, 1H), 7.48-7.41 (m, 2H), 7.36 (d , 1H), 7.10 (d, 1H), 3.86 (s, 3H), 3.77-3.70 (m, 1H), 3.68-3.42 (m, 3H), 2.61-2.52 (m, 1H), 2.13-2.02 (m , 1H), 1.84-1.75 (m, 4H), 1.75-1.68 (m, 2H), 1.68-1.59 (m, 2H), 1.54-1.33 (m, 5H), 1.14-1.03 (m, 4H), 1.02 -0.92 (m, 2H), 0.90-0.72 (m, 11H), -0.03 (s, 6H); LCMS: 684.2 [M+H]+ .step 2 : opposite - N -( 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- N -(( opposite - 4 -( 3 - fluorine - 1 - methyl - 1 h - Indazole - 5 - base ) Cyclohexyl ) methyl )- 4 - Hydroxycyclohexanecarboxamide Aqueous hydrochloric acid (1 N, 0.5 mL, 0.5 mmol) was added to trans-4-((tert-butyldimethylsilyl)oxy)-N -(3-(1-Cyclopropyl-1h -pyrazol-4-yl)phenyl)-N -((trans-4-(3-fluoro-1-methyl-1h -indazol-5-yl)cyclohexyl)methyl)cyclohexanecarboxamide (180 mg, 0.263 mmol), THF (1 mL) and MeOH (1 mL). After 10 minutes, the ice bath was removed, and the reaction was stirred for 50 minutes. The mixture was diluted with EtOAc (20 mL), washed (2 × 20 mL saturated NaHCO3 , and then 20 mL of brine), dried (Na2 SO4 ), filtered and concentrated. The residue was purified by silica gel chromatography (0% to 5% MeOH/DCM) to give trans-N -(3-(1-Cyclopropyl-1h -pyrazol-4-yl)phenyl)-N -((trans-4-(3-fluoro-1-methyl-1h -indazol-5-yl)cyclohexyl)methyl)-4-hydroxycyclohexylcarboxamide (150 mg, 100%, purity 95%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.54 (s, 1H), 7.50 (dd, 1H), 7.48-7.41 (m, 2H), 7.36 (dd , 1H), 7.10 (d, 1H), 4.38 (d, 1H), 3.86 (s, 3H), 3.77-3.70 (m, 1H), 3.68-3.43 (m, 2H), 3.31-3.20 (m, 1H ), 2.61-2.52 (m, 1H), 2.16-2.00 (m, 1H), 1.84-1.68 (m, 6H), 1.68-1.59 (m, 2H), 1.52-1.33 (m, 5H), 1.15-1.04 (m, 4H), 1.02-0.96 (m, 2H), 0.81-0.67 (m, 2H); LCMS: 570.4 [M+H]+ . follow forcompound 5 The described procedure synthesized the following compounds from appropriate intermediates.
Figure AA27
Figure AA28
Figure AA29
Figure AA30
Figure AA31
 Alternative Conditions: Step 1:1 The solvent is DCM;2 DMAP, pyridine, 80°C;3 TEA, DCM, room temperature;4 DMAP, TEA, 80°C, 1 hour; step 2:5 3M HCl, THF, MeOH, 45°C.6 TBS is cleaved during acylation.7 Isolated during the purification of compound 5.27.compound 6 opposite - N -( 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- 4 - hydroxyl - N -(( 4 -( 4 - Methoxy - 3 - methyl phenyl ) Shuanghuan [ 2 . 2 . 2 ] pungent - 1 - base ) methyl ) Cyclohexaneformamide
Figure 02_image513
step 1 : opposite - 4 -(( tertiary butyldimethylsilyl ) Oxygen )- N -( 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- N -(( 4 -( 4 - Methoxy - 3 - methyl phenyl ) Shuanghuan [ 2 . 2 . 2 ] pungent - 1 - base ) methyl ) Cyclohexaneformamide at room temperature willintermediate 8 (44 mg/mL toluene solution, 2.5 mL, 0.397 mmol) was added tointermediate 7 (114 mg, 0.258 mmol), pyridine (0.1 mL, 1.2 mmol) and DCM (2.0 mL). The mixture was stirred at room temperature for 135 minutes, and additionalintermediate 8 (44 mg/mL solution in toluene, 0.5 mL, 0.079 mmol). The mixture was stirred for 90 min, diluted with EtOAc (20 mL), washed (2 x 15 mL saturated NaHCO3 , and then 15 mL of brine), dried (Na2 SO4 ), filtered and concentrated. The residue was purified by silica gel chromatography (0% to 35% EtOAc/hexanes) to afford trans-4-((t-butyldimethylsilyl)oxy)- as a white foamN -(3-(1-Cyclopropyl-1h -pyrazol-4-yl)phenyl)-N - ((4-(4-Methoxy-3-methylphenyl)bicyclo[2.2.2]oct-1-yl)methyl)cyclohexanecarboxamide (155 mg, 88%). LCMS: 682.5 [M+H]+ .step 2 : opposite - N -( 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- 4 - hydroxyl - N -(( 4 -( 4 - Methoxy - 3 - methyl phenyl ) Shuanghuan [ 2 . 2 . 2 ] pungent - 1 - base ) methyl ) Cyclohexaneformamide Aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) was added to trans-4-((tert-butyldimethylsilyl)oxy)-N -(3-(1-Cyclopropyl-1h -pyrazol-4-yl)phenyl)-N -((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]oct-1-yl)methyl)cyclohexanecarboxamide (150 mg, 0.220 mmol), THF ( 1 mL) and MeOH (1 mL). The reaction was stirred for 1 h, diluted with EtOAc (20 mL), washed (2 x 20 mL saturated NaHCO3 , and then 20 mL of brine), dried (Na2 SO4 ), filtered and concentrated. The residue was purified by silica gel chromatography (0% to 5% MeOH/DCM) to give trans-N -(3-(1-Cyclopropyl-1h -pyrazol-4-yl)phenyl)-4-hydroxyl-N - ((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]oct-1-yl)methyl)cyclohexanecarboxamide (109 mg, 89%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 7.94 (s, 1H), 7.59 (s, 1H), 7.54 (d, 1H), 7.40 (t, 1H), 7.16 (d, 1H), 7.03-6.97 (m , 2H), 6.76 (d, 1H), 4.40 (s, 1H), 3.76-3.71 (m, 2H), 3.70 (s, 3H), 3.62-3.32 (m, 1H), 3.31-3.20 (m, 1H ), 2.22-2.11 (m, 1H), 2.08 (s, 3H), 1.80-1.68 (m, 2H), 1.66-1.55 (m, 8H), 1.46-1.31 (m, 8H), 1.11-0.99 (m , 4H), 0.83-0.66 (m, 2H); LCMS: 568.4 [M+H]+ . follow forcompound 6 The described procedure synthesized the following compounds from appropriate intermediates.
Figure AA32
 Alternative Conditions: Step 1:1 DMAP and pyridine are used as solvents;2 50°C.compound 7 opposite - 4 - Amino - N -( 3 -( 1 - Isopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl ) Cyclohexaneformamide
Figure 02_image519
step 1 : ( opposite - 4 -(( 3 -( 1 - Isopropyl - 1 h - pyrazole - 4 - base ) Phenyl )(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl ) carbamoyl ) Cyclohexyl ) tertiary butyl carbamate at room temperature willintermediate 8 . 02 (58 mg/mL in toluene, 9 mL, 2.006 mmol) was added tointermediate 7 . twenty one (418 mg, 1.001 mmol), pyridine (0.33 mL, 4.08 mmol) and DCM (4 mL). The resulting mixture was stirred at room temperature for 60 min, diluted with 50 mL EtOAc, washed (50 mL H2 O, 50 mL saturated NaHCO3 , and then 50 mL of brine), dried (Na2 SO4 ), filtered, and then concentrated. The residue was purified by silica gel chromatography (10% to 50% EtOAc/hexanes) to afford (trans-4-((3-(1-isopropyl-1h -pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate Butyl ester (622 mg, 96%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.32 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.55-7.52 (m, 1H), 7.44 (t, 1H), 7.09 (d, 1H), 6.98-6.92 (m, 2H), 6.81-6.75 (m, 1H), 6.53 (d, 1H), 4.56-4.44 (m, 1H), 3.71 (s, 3H), 3.68-3.35 (m, 2H), 3.20-3.00 (m, 1H), 2.38-2.28 (m, 1H), 2.12-2.00 (m, 4H), 1.80-1.62 (m, 8H), 1.50-1.21 (m, 20H), 1.13-0.98 (m, 2H) , 0.89-0.79 (m, 2H); LCMS: 665.5 [M+Na]+ .step 2 : opposite - 4 - Amino - N -( 3 -( 1 - Isopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- N -(( opposite - 4 -( 4 - Methoxy - 3 - methyl phenyl ) Cyclohexyl ) methyl ) Cyclohexaneformamide Stir at room temperature (trans-4-((3-(1-isopropyl-1h -pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate A solution of butyl ester (617 mg, 0.960 mmol) and trifluoroacetic acid (20% in DCM, 10 mL) was diluted with DCM (50 mL) for 35 min, and washed (2×50 mL saturated NaHCO3 , and then 50 mL of saline). dry (Na2 SO4 ) organic layer, filtered, and then concentrated to give trans-4-amino-N -(3-(1-isopropyl-1h -pyrazol-4-yl)phenyl)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (515 mg, 99%).1 H NMR (400 MHz, DMSO-d 6 ): δ 8.32 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.56-7.52 (m, 1H), 7.44 (t, 1H), 7.09 (d, 1H), 6.97-6.92 (m, 2H), 6.80-6.76 (m, 1H), 4.56-4.44 (m, 1H), 3.71 (s, 3H), 3.66-3.37 (m, 2H), 3.11-2.87 (m, 2H), 2.48 -2.40 (m, 1H), 2.38-2.28 (m, 1H), 2.13-2.00 (m, 4H), 1.80-1.60 (m, 8H), 1.49-1.35 (m, 9H), 1.35-1.21 (m, 2H), 1.13-0.99 (m, 2H), 0.77-0.60 (m, 2H); LCMS: 543.6 [M+H]+ . follow forcompound 7 The procedure described is provided byintermediate 7 Synthesize the following compounds.
Figure AA33
 compound 8 opposite - N -( 3 -( 1 - Cyclopropyl - 1 h - pyrazole - 4 - base ) Phenyl )- 4 - hydroxyl - N -(( opposite - 4 -( 4 - hydroxyl - 3 - methyl phenyl ) Cyclohexyl ) methyl ) Cyclohexaneformamide
Figure 02_image523
BBr at 30 °C for 2 min3 (4.0 mL, 1M in DCM) was added dropwise tocompound 3 (1.007 g, 1.858 mmol) and anhydrous DCM (40 mL). The reaction became thick with a white lumpy solid and was stirred vigorously. After 6 hours, additional DCM (5 mL) and BBr were added3 (1 mL). After 24 hours total reaction time, add CH3 OH/H2 O mixture (20 mL, 19:1). The reaction was concentrated, and then purified by silica gel chromatography (1% to 20% CH3 OH in DCM) to give a mixture containing secondary amines (deacylation). By reverse phase HPLC (Waters SunFire column; 55% CH3 CN/45%H2 (2, containing 0.1% TFA) this mixture was purified and the concentrated fractions were diluted with EtOAc (60 mL) and washed with saturated NaHCO3 (50 mL) to wash. dry (MgSO4 ) organic layer, filtered, concentrated, and then kept under vacuum (0.1 mTorr) for several days to give the reaction as a white foam-N -(3-(1-Cyclopropyl-1h -pyrazol-4-yl)phenyl)-4-hydroxyl-N -((trans-4-(4-hydroxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide.1 H NMR (400 MHz, DMSO-d 6 ): d 8.92 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.53 (s, 1H), 7.44 (t, 1H), 7.08 (d, 1H ), 6.85 (s, 1H), 6.77 (d, 1H), 6.63 (d, 1H), 4.38 (d, 1H), 3.78-3.71 (m, 1H), 3.55 (br, 2H), 3.32-3.21 ( m, 1H), 2.33-2.23 (m, 1H), 2.06 (s, 3H), 2.08-1.99 (m, 1H), 1.79-1.67 (m, 6H), 1.67-1.58 (m, 2H), 1.48- 1.33 (m, 3H), 1.33-1.20 (m, 2H), 1.10-0.95 (m, 6H), 0.81-0.68 (m, 2H); LCMS: 528.4 [M+H]+ .example A-1 : parenteral pharmaceutical composition For the preparation of parenteral pharmaceutical compositions suitable for administration by injection (subcutaneous, intravenous), 1 to 1000 mg of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water , and then mixed with 10 mL of 0.9% sterile saline. Add a suitable buffer and optionally an acid or base to adjust the pH. The mixture is incorporated into unit dosage forms suitable for administration by injection.example A-2 : oral solution To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer, optional buffer, and taste-masking excipient), a 20 mg/mL solution was obtained.example A-3 : oral lozenge By mixing 20 to 50% by weight of a compound described herein or a pharmaceutically acceptable salt thereof, 20 to 50% by weight of microcrystalline cellulose, 1 to 10% by weight of low-substituted hydroxypropyl cellulose and 1 to 10% by weight % by weight magnesium stearate or other suitable excipients to prepare lozenges. Lozenges are prepared by direct compression. The total weight of the compressed lozenges is maintained at 100 to 500 mg.example A-4 : Oral capsule To prepare a pharmaceutical composition for oral delivery, 10 to 500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into oral dosage units suitable for oral administration, such as hard gelatin capsules. In another embodiment, 10 to 500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is placed in a size 4 capsule or a size 1 capsule (hypromellose or hard gelatin) and the capsule is made closure.example A-5 : surface gel composition To prepare a pharmaceutical topical gel composition, a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with hydroxypropylcellulose, propylene glycol, isopropyl myristate and purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, suitable for topical administration.example B-1 : in vitro FXR analyze ( TK ) inoculation CV-1 cells were seeded at a density of 2,000,000 cells in T175 flasks with DMEM + 10% charcoal double-stripped FBS at 37 °C in 5% CO2 Medium incubation lasted 18 hours (O/N).transfection After incubation for 18 hours, the medium in the T175 flask was replaced with fresh DMEM + 10% charcoal super-stripped serum. In polypropylene tubes, 2500 μL of OptiMEM (Life Technologies, Cat# 31985-062) was combined with expression plasmids for hFXR, hRXR, TK-ECRE-luc, and pCMX-YFP. The tubes were then vortexed briefly and incubated at room temperature for 5 minutes. Transfection reagent (X-tremeGENE HP from Roche, cat. no. 06 366 236 001) was added to the vortexed OptiMEM/plastid mixture and incubated at room temperature for 20 minutes. After incubation, the transfection agent/DNA mix complex was added to the cells in T175 flasks and incubated at 37°C in 5% CO2 Cells were incubated in medium for 18 hours (O/N).test compound Compounds were serially diluted in DMSO and added to transfected CV-1 cells. Cells were then incubated for 18 hours. The next day, cells were lysed and examined by fluorescence. Representative data for exemplary compounds disclosed herein are presented in the table below.surface 2
Figure 107108918-A0304-0001
 Among them, "+++" means EC50 ≤0.25 μM; "++" means EC50 > 0.25 μM and < 1 μM; "+" means EC50 ≥ 1 μM. Compounds with <25% of the maximum efficacy of the Fexarmine control group were classified as "+".example B-2 : in vitro FXR analyze (hSHP) inoculation CV-1 cells were seeded at a density of 2,000,000 cells in T175 flasks with DMEM + 10% charcoal double-stripped FBS at 37 °C in 5% CO2 Medium incubation lasted 18 hours (O/N).transfection After incubation for 18 hours, the medium in the T175 flask was replaced with fresh DMEM + 10% charcoal super-stripped serum. In polypropylene tubes, 2500 μL of OptiMEM (Life Technologies, Cat# 31985-062) was combined with expression plasmids for hFXR, hRXR, hSHP-luc, and pCMX-YFP. The tubes were then vortexed briefly and incubated at room temperature for 5 minutes. Transfection reagent (X-tremeGENE HP from Roche, cat. no. 06 366 236 001) was added to the vortexed OptiMEM/plastid mixture and incubated at room temperature for 20 minutes. After incubation, the transfection agent/DNA mix complex was added to the cells in T175 flasks and incubated at 37°C in 5% CO2 Cells were incubated in medium for 18 hours (O/N).test compound Compounds were serially diluted in DMSO and added to transfected CV-1 cells. Cells were then incubated for 18 hours. The next day, cells were lysed and examined by fluorescence.example B-3 : NASH activity study ( STZ Model ) induced NASH in male C57BL/6 by a single subcutaneous injection of 200 μg STZ 2 days after birth, followed by feeding a high-fat diet (HFD) ad libitum after 4 weeks of age. While continuing the HFD, compounds can be dosed for 4 to 8 weeks to determine the effect on NASH. Fasting glucose can be measured throughout the study with a handheld glucose meter. Serum alanine transaminase (ALT), aspartate transaminase (AST) and triglyceride (TG) can be measured by clinical chemistry analyzer. TG content in liver tissue can be measured using Triglyceride E Test Kit (Wako, Tokyo, Japan). Histological analysis of liver sections can be performed on tissue embedded in Tissue-TEK O.C.T. compound, flash frozen in liquid nitrogen, and stored at -80°C. Sections (5 μm) can be cut, air-dried and fixed in acetone. For hematoxylin and eosin staining, liver sections can be prefixed by Bouin's solution and then stained with hematoxylin and eosin solution. Sirius red staining can be used to assess (zone 3) the degree of liver fibrosis.example B-4 : NASH activity study ( AMLN Model ) By using the AMLN diet (DIO-NASH) (D09100301, Research Diet, USA) (40% fat (18% trans fat), 40% carbohydrates (20% fructose) and 2% cholesterol) for diet induction and in male NASH was induced in C57BL/6 mice. Animals were kept on diet for 29 weeks. After 26 weeks of dietary induction, liver biopsies were performed for baseline histological assessment of disease progression (fatty liver and fibrosis), graded according to fibrosis stage, steatosis score and body weight and randomized into treatment groups. Three weeks after the biopsy, mice were divided into treatment groups and dosed daily with FXR agonists by oral gavage for 8 weeks. At the end of the study, liver biopsies were performed to assess hepatic steatosis and fibrosis by examining tissue sections stained with H&E and Sirius red, respectively. Total collagen content in the liver was measured by acid hydrolysis of collagen by colorimetric assay of hydroxyproline residues. Triglyceride and total cholesterol content in liver tissue homogenates were measured in a single assay using an automated analyzer Cobas C-111 and a commercially available kit (Roche Diagnostics, Germany) according to the manufacturer's instructions.example B-5 : CCl4 fibrosis model CCl can be administered by intraperitoneal injection every two weeks4 Whereas fibrosis was induced in BALB/c male mice. Mix CCl 1:14 Formulated in oil and injected intraperitoneally at 1 ml/kg. After 2 to 4 weeks of induction of fibrosis, compound can be administered daily by oral gavage for 2 to 6 weeks of treatment while continuing to administer CCl4 . At study termination, livers can be formalin fixed and stained with Sirius red stain for histopathological assessment of fibrosis. Total collagen content can be measured by acid hydrolysis of collagen by colorimetric determination of hydroxyproline residues. Serum alanine transaminase (ALT) and aspartate transaminase (AST) can be measured by clinical chemistry analyzer.example B-6 : Intrahepatic cholestasis model Experimental intrahepatic cholestasis induced by 17a-ethinylestradiol (EE2) treatment in rodents is a commonly used in vivo model for examining mechanisms involved in estrogen-induced cholestasis. Intrahepatic cholestasis can be induced in adult male mice by daily subcutaneous injection of 10 mg/kg 17a-ethinylestradiol (E2) for 5 days. Testing of FXR ligands can be performed by administering compounds during E2-induced cholestasis. Cholestatic effects can be quantified by assessing the liver/body weight ratio and measuring serum total bile acids, and bases can be measured using reagents and controls from Diagnostic Chemicals and a Cobas Mira plus CC analyzer (Roche Diagnostics) Sexual phosphatase levels. For histology and mitotic measurements, liver samples from each mouse can be fixed in 10% neutral buffered formalin. Slides were stained with hematoxylin and eosin using standard protocols and examined microscopically for structural changes. Hepatocyte proliferation was assessed by immunohistochemical staining for Ki67.example B-7 : direct target gene regulation Regulation of direct target genes by FXR ligands can be assessed by dosing mice with compounds either short-term or chronically and collecting tissue at various time points after dosing. RNA can be isolated from tissues such as ileum and liver and reverse transcribed into cDNA for quantitative PCR of genes known in the literature, such as SHP, BSEP, IBABP, FGF15, CYP7A1, CYP8B1 and C3, directly and indirectly regulated by FXR analyze.example B-8 : mouse PK Research Plasma pharmacokinetics of any of the compounds disclosed herein as test articles were measured following single intravenous and oral bolus administration to mice (CD-1, C57BL, and diet-induced obese mice) study. Test articles are formulated for intravenous administration in a vehicle solution of DMSO, PEG400, hydroxypropyl-β-cyclodextrin (HPβCD) and administered at selected doses (eg, in a dose volume of 3 mL/kg). Formulations for oral administration are prepared in a suitable oral administration vehicle (vegetable oil, PEG400, Solutol, citrate buffer, or carboxymethylcellulose) and administered at the selected dose in a dose volume of 5 to 10 mL/kg and. Blood samples (approximately 0.15 mL) were collected at predetermined time intervals in tubes containing EDTA by the buccal pouch method after intravenous or oral administration. Plasma was separated by centrifugation of blood at 10,000 g for 5 minutes, and aliquots were transferred to 96-well plates and stored at -60°C or less prior to analysis. Calibration standards for the test articles were prepared by diluting DMSO stock solutions with DMSO over a range of concentrations. Aliquots of calibration standards in DMSO were pooled with plasma from untreated mice such that the final concentration of calibration standards in plasma was 10-fold less than calibration standards in DMSO. PK plasma samples were pooled with blank DMSO to match the matrix. Calibration standards and PK samples were combined with ice-cold acetonitrile containing an analytical internal standard and centrifuged at 1850 g for 30 minutes at 4°C. Supernatant fractions were analyzed by LC/MS/MS and quantified against a calibration curve. Pharmacokinetic parameters (area under the curve (AUC), Cmaximum , Tmaximum , Elimination half-life (T1 / 2 ) clearance (CL), steady-state volume of distribution (Vdss ) and mean residence time (MRT)).example B-9 : the rat ANIT Model The compounds described herein are evaluated in a long-term therapeutic model of cholestasis over a range of doses (eg, doses ranging from 0.01 to 100 mg/kg). This model is used to assess the suitability of using FXR agonists, such as the compounds described herein, to treat cholestatic liver disorders such as: bile acid malabsorption (eg, primary or secondary bile acid diarrhea), bile Reflux gastritis, collagenous colitis, lymphocytic colitis, diversion colitis, indeterminate colitis, Alagille syndrome, biliary atresia, liver transplant rejection with disappearing bile ducts, bone marrow Or graft-versus-host disease associated with stem cell transplantation, cystic fibrosis liver disease, and liver disease associated with parenteral nutrition. Rats were treated with α-naphthyl isothiocyanate (ANIT) (0.1% w/w) in food for 3 days, and then treated with a compound described herein at a series of doses (for example, between 0.01 and 100 mg/kg range) treatment. The non-cholestatic control group was fed a standard diet without ANIT and served as non-cholestatic control animals ("control"). After 14 days of oral dosing, rat sera were analyzed for analyte levels. LLQ, lower limit of quantitation. Mean ± SEM; n = 5. Levels of indicators of hepatobiliary damage, such as elevated levels of circulating aspartate transaminase (AST), alanine transaminase (ALT), bilirubin and bile acids, were measured in rat serum. ANIT exposure induces profound cholestasis and hepatocellular injury. Compounds that modify many of these indicators are useful in the treatment of the aforementioned diseases or conditions. The decreased accumulation of bile acids in the liver, enhanced secretion of bile acids in the biliary tract, and inhibition of bile acid synthesis are consistent with the pharmacological effects of FXR agonists. Improvement in serum conjugated bilirubin, a direct indicator of liver function, suggests recovery from cholestasis with improved bile secretion. In addition, assays were performed to determine the effect of the compounds described herein on serum FGF15 fibroblast growth factor 15 (FGF15 in rodents; FGF19 in humans) expression, hormone secreted in portal blood and for synergistic inhibition of CYP7A1 expression with SHP effects on liver signaling. The direct FXR-dependent induction of FGF15/19 together with the anti-cholestasis of FGF15/19 make it a suitable serum biomarker for detecting the targeting involvement of FXR agonists. Serum FGF15 levels were quantified using the FGF15 Meso Scale Discovery (MSD) assay. For example, the mouse FGF15 antibody (AF6755) from R&D Systems was used as both capture and detector antibody in the assay. FGF15 antibody was labeled using MSD SULFO-TAG NHS-Ester (MSD SULFO-TAG NHS-Ester). MSD standard 96-well plates were coated with FGF15 capture antibody and the plates were blocked with MSD Blocker A (R93AA-2). After washing the plate with PBS + 0.05% Tween 20, MSD Diluent 4 was dispensed into each well and incubated for 30 minutes. 25 pi calibrator dilutions or samples (serum or EDTA plasma) were dispensed into each well and incubated with shaking at room temperature. After washing, detection antibody was added and incubated with shaking for 1 hour at room temperature. Plates were read on an MSD SECTOR Imager 6000 after washing and addition of MSD Read Buffer (R92TC-2). Use MSD data analysis software to calculate the standard curve and the graph of unknown samples. The examples and embodiments described herein are for the purpose of illustration only, and various modifications or changes proposed by those skilled in the art will be included in the spirit and scope of the application and the scope of the appended claims.example B-10 : chronic DSS colitis model The therapeutic potential of compounds against inflammatory bowel disease (IBD) can be tested using chronic dextran sodium sulfate (DSS) induced mice. Chronic colitis can be induced by feeding DSS to mice in drinking water. For example, 2% DSS in drinking water for 5 days and normal drinking water for 5 days, then this feeding cycle can be repeated two more times with higher DSS concentrations of 2.5% and 3%, respectively, for a total of three cycles. Colitis develops approximately after the first DSS feeding cycle, which can be monitored by weight loss, stool firmness, and rectal bleeding. FXR agonists can be tested by administering the FXR agonist to mice at the same time as starting a 2% DSS water feed. Alternatively, testing of FXR agonists can be performed after the first feeding cycle of 2% DSS water and plain water. During administration of FXR agonists to mice, the therapeutic effect can be monitored by observation of body weight, stool firmness, and rectal bleeding. Following euthanasia, disease development and the effects of FXR agonists can be assessed by measuring colon weight and length, colon histology using H&E staining for inflammation and structural changes in the mucosa, and protein and RNA expression of genes associated with the disease be further quantified.example B-11 : acceptability T Cell Transfer Colitis Mouse Model The recipient T cell transfer colitis model is recognized as a relevant mouse model of human inflammatory bowel disease (IBD). To induce colitis in this model, CD4 T lymphocyte populations were isolated from the spleens of donor mice, followed by purification of a subset of CD4+CD45RB high T cells by cell sorting using flow cytometry. Purified CD4+CD45RB high T cells were injected into the peritoneal cavity of mice receiving SCID. Colitis develops approximately three to six weeks after T cell transfer, which can be monitored by weight loss (although the amount of weight loss can vary), loose stools, or bloody diarrhea. Testing of FXR agonists can be initiated simultaneously with injection of purified CD4+CD45RB high T cells into SCID-receiving mice. Alternatively, FXR agonists can be administered two or three weeks after T cell transfer, when colitis has developed in this model. During administration of FXR agonists to mice, the therapeutic effect can be monitored by observation of body weight, stool firmness, and rectal bleeding. Following euthanasia, disease development and the effects of FXR agonists can be assessed by measuring colon weight and length, colon and ileal histology stained by H&E for inflammation and structural changes in the mucosa, and proteins of genes associated with the disease and RNA performance was further quantified.example B-12 : Mdr1a -/- mouse model The Mdr1a-/- mouse model is a spontaneous colitis model that has been used to test novel therapies for human IBD. Deletion of the Mdr1a gene in this model results in impaired gut barrier function, leading to increased infiltration of gut bacteria and subsequent colitis. Under proper housing conditions, Mdr1a-/- mice can develop colitis at about 8 to 13 weeks of age. During disease progression, the Disease Activity Index (DAI), which sums clinically observed scores for rectal prolapse, stool firmness, and rectal bleeding, can be used to monitor disease. Testing of FXR agonists can be initiated at the initial stage of the disease, typically with a DAI score below 1.0. Alternatively, administration of the FXR agonist can be initiated when colitis is already present, usually with a DAI score greater than 2.0. The therapeutic effect of an FXR agonist can be monitored by measuring DAI, and testing can be terminated when the desired disease severity has been achieved, typically with a DAI score of about 5.0. Following euthanasia, disease development and the effects of FXR agonists can be assessed by measuring colon weight and length, colon histology using H&E staining for inflammation and structural changes in the mucosa, and protein and RNA expression of genes associated with the disease be further quantified. The examples and embodiments described herein are for the purpose of illustration only, and various modifications or changes proposed by those skilled in the art will be included in the spirit and scope of the application and the scope of the appended claims.

Figure 107108918-A0101-11-0002-1
Figure 107108918-A0101-11-0002-1

Claims (20)

一種具有式(I)結構之化合物或其醫藥學上可接受之鹽，
Figure 107108918-A0305-02-0185-1
 其中，X1為CH或N；R1為H、D、鹵素、-CN、-OH、-N(R15)2、-NR15S(=O)2(C1-C4烷基)、-OC(=O)(C1-C4烷基)、-CO2H、-CO2(C1-C4烷基)、-C(=O)N(R15)2、-NR15C(=O)(C1-C4烷基)、-NR15C(=O)O(C1-C4烷基)、-OC(=O)N(R15)2、-NR15C(=O)N(R15)2、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、C1-C4氘代烷基、C1-C4氘代烷氧基、C1-C4氟烷基、C1-C4氟烷氧基、C1-C4雜烷基或經取代或未經取代之單環C2-C5雜環烷基；X2為CR2或N；R2為H、D、鹵素、-CN、-OH、-N(R15)2、-NR15S(=O)2(C1-C4烷基)、-OC(=O)(C1-C4烷基)、-CO2H、-CO2(C1-C4烷基)、-C(=O)N(R15)2、-NR15C(=O)(C1-C4烷基)、-NR15C(=O)O(C1-C4烷基)、-OC(=O)N(R15)2、-NR15C(=O)N(R15)2、C1-C4烷基、C2-C4烯 基、C2-C4炔基、C1-C4烷氧基、C1-C4氘代烷基、C1-C4氘代烷氧基、C1-C4氟烷基、C1-C4氟烷氧基或C1-C4雜烷基；或R1及R2與插入原子一起形成經取代或未經取代之5員稠環，在該環中具有0至3個N原子及0至2個O或S原子；X3為CR3或N；R3為H、D、鹵素、-CN、-OH、-N(R15)2、-NR15S(=O)2(C1-C4烷基)、-OC(=O)(C1-C4烷基)、-CO2H、-CO2(C1-C4烷基)、-C(=O)N(R15)2、-NR15C(=O)(C1-C4烷基)、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、C1-C4氘代烷基、C1-C4氘代烷氧基、C1-C4氟烷基、C1-C4氟烷氧基、或C1-C4雜烷基；各X4獨立地為CH或N；R4為H、D、F或-CH3；R5為H、D、F或-CH3；或R4及R5一起形成橋鍵，其為-CH2-或-CH2CH2-；各R6獨立地為H、D、F、-OH或-CH3；m為0、1或2；R7為H、D、鹵素、-CN、-OH、C1-C4烷基、C1-C4烷氧基、C1-C4氘代烷基、C1-C4氘代烷氧基、C1-C4氟烷基、C1-C4氟烷氧基或C1-C4雜烷基；L不存在、為-Y2-L1-、-L1-Y2-、伸環丙基、伸環丁基或雙環[1.1.1]伸戊基；Y2不存在、為-O-、-S-、-S(=O)-、-S(=O)2-、-S(=O)2NR15-、-CH2-、-CH=CH-、-C≡C-、-C(=O)-、-C(=O)O-、-OC(=O)-、- OC(=O)O-、-C(=O)NR15-、-NR15C(=O)-、-OC(=O)NR15-、-NR15C(=O)O-、-NR15C(=O)NR15-、-NR15S(=O)2-或-NR15-；L1不存在或為經取代或未經取代之C1-C4伸烷基；X5為NR8或N；R8為H、D、C1-C6烷基、C1-C6氘代烷基、C1-C6氟烷基、C1-C6雜烷基、-C(=O)(C1-C4烷基)、-CO2(C1-C4烷基)、-C(=O)N(R15)2、-S(=O)2(C1-C4烷基)、-S(=O)2N(R15)2、經取代或未經取代之C3-C6環烷基或經取代或未經取代之單環C2-C6雜環烷基、經取代或未經取代之苯基或經取代或未經取代之單環雜芳基；R9為H、D、F或-CH3；Y為-CR10R11-、-O-、-S-、-S(=O)-、-S(=O)2-或-NR17-；R10為H、D、鹵素、-CN、-OH、C1-C6烷基、C1-C6烷氧基、C1-C6氟烷基、-SR12、-S(=O)R14、-S(=O)2R14、或-N(R12)2；R11為H、D、F或-CH3；或R9及R11一起形成橋鍵，其為-CH2-或-CH2CH2-；各R12獨立地為H、C1-C4烷基、C1-C4氘代烷基、C1-C4氟烷基、C1-C4雜烷基、經取代或未經取代之C3-C6環烷基、經取代或未經取代之C2-C6雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基、經取代或未經取代之單環雜芳基；R14為C1-C4烷基、C1-C4氘代烷基、C1-C4氟烷基、C1-C4雜烷基、經取代或未經取代之C3-C6環烷基、經取代或未經取代之C2-C6雜環烷基、經取代或未經取代之苯基、經取代或未經取代之苯甲基或經取代或未經取代之單環雜芳基； R15為H或經取代或未經取代之C1-C6烷基；各R16獨立地為H、D、鹵素、-CN、-OH、-N(R15)2、-NR15S(=O)2(C1-C4烷基)、-S(C1-C4烷基)、-S(=O)2(C1-C4烷基)、-C(=O)(C1-C4烷基)、-OC(=O)(C1-C4烷基)、-CO2H、-CO2(C1-C4烷基)、-NR15C(=O)(C1-C4烷基)、-C(=O)N(R15)2、-NR15C(=O)O(C1-C4烷基)、-OC(=O)N(R15)2、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4烷氧基、C1-C4氘代烷基、C1-C4氘代烷氧基、C1-C4氟烷基、C1-C4氟烷氧基、C1-C4雜烷基、經取代或未經取代之C3-C6環烷基、經取代或未經取代之單環C2-C6雜環烷基、經取代或未經取代之苯基或經取代或未經取代之單環雜芳基；n為0、1或2；R17為-L5-R14；及L5不存在、為-S(=O)2-、-C(=O)-、-CO2-或-C(=O)N(R15)-；其中該術語「經取代」意謂所提及之基團經一或多個其他基團取代，該(等)基團獨立地選自D、鹵素、-CN、-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2(C1-C4烷基)、-C(=O)NH2、-C(=O)NH(C1-C4烷基)、-C(=O)N(C1-C4烷基)2、-S(=O)2NH2、-S(=O)2NH(C1-C4烷基)、-S(=O)2N(C1-C4烷基)2、C1-C4烷基、C3-C6環烷基、C1-C4氟烷基、C1-C4雜烷基、C1-C4烷氧基、C1-C4氟烷氧基、-SC1-C4烷基、-S(=O)C1-C4烷基及-S(=O)2C1-C4烷基。 A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
Figure 107108918-A0305-02-0185-1
 Wherein, X 1 is CH or N; R 1 is H, D, halogen, -CN, -OH, -N(R 15 ) 2 , -NR 15 S(=O) 2 (C 1 -C 4 alkyl) , -OC(=O)(C 1 -C 4 alkyl), -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -C(=O)N(R 15 ) 2 , -NR 15 C(=O)(C 1 -C 4 alkyl), -NR 15 C(=O)O(C 1 -C 4 alkyl), -OC(=O)N(R 15 ) 2 , -NR 15 C(=O)N(R 15 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuteroalkyl, C 1 -C 4 deuteroalkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 heteroalkyl or substituted or unsubstituted Substituted monocyclic C 2 -C 5 heterocycloalkyl; X 2 is CR 2 or N; R 2 is H, D, halogen, -CN, -OH, -N(R 15 ) 2 , -NR 15 S( =O) 2 (C 1 -C 4 alkyl), -OC(=O)(C 1 -C 4 alkyl), -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -C (=O)N(R 15 ) 2 , -NR 15 C(=O)(C 1 -C 4 alkyl), -NR 15 C(=O)O(C 1 -C 4 alkyl), -OC (=O)N(R 15 ) 2 , -NR 15 C(=O)N(R 15 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuterated alkyl, C 1 -C 4 deuterated alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy or C 1 - C4heteroalkyl ; or R1 and R2 together with intervening atoms form a substituted or unsubstituted 5-membered fused ring having 0 to 3 N atoms and 0 to 2 O or S in the ring atom; X 3 is CR 3 or N; R 3 is H, D, halogen, -CN, -OH, -N(R 15 ) 2 , -NR 15 S(=O) 2 (C 1 -C 4 alkyl ), -OC(=O)(C 1 -C 4 alkyl), -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -C(=O)N(R 15 ) 2 , - NR 15 C(=O)(C 1 -C 4 alkyl), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuterated alkyl, C 1 -C 4 deuterated alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 heteroalkyl; Each X 4 is independently CH or N; R 4 is H, D, F or -CH 3 ; R 5 is H, D, F or -CH 3 ; or R 4 and R 5 together form a bridge bond, which is - CH 2 -or -CH 2 CH 2 -; each R 6 is independently H, D, F, -OH or -CH 3 ; m is 0, 1 or 2; R 7 is H, D, halogen, -CN, -OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 deuterated alkyl, C 1 -C 4 deuterated alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy or C 1 -C 4 heteroalkyl; L does not exist, is -Y 2 -L 1 -, -L 1 -Y 2 -, cyclopropyl, cyclobutyl or Bicyclo[1.1.1]pentyl; Y 2 does not exist, it is -O-, -S-, -S(=O)-, -S(=O) 2 -, -S(=O) 2 NR 15 -, -CH 2 -, -CH=CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O) O-, -C(=O)NR 15 -, -NR 15 C(=O)-, -OC(=O)NR 15 -, -NR 15 C(=O)O-, -NR 15 C(= O) NR 15 -, -NR 15 S(=O) 2 - or -NR 15 -; L 1 is absent or is substituted or unsubstituted C 1 -C 4 alkylene; X 5 is NR 8 or N; R 8 is H, D, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, -C(=O )(C 1 -C 4 alkyl), -CO 2 (C 1 -C 4 alkyl), -C(=O)N(R 15 ) 2 , -S(=O) 2 (C 1 -C 4 Alkyl), -S(=O) 2 N(R 15 ) 2 , substituted or unsubstituted C 3 -C 6 cycloalkyl or substituted or unsubstituted monocyclic C 2 -C 6 heterocycle Alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; R 9 is H, D, F or -CH 3 ; Y is -CR 10 R 11 -, -O -, -S-, -S(=O)-, -S(=O) 2- or -NR 17 -; R 10 is H, D, halogen, -CN, -OH, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkyl, -SR 12 , -S(=O)R 14 , -S(=O) 2 R 14 , or -N(R 12 ) 2 ; R 11 is H, D, F or -CH 3 ; or R 9 and R 11 together form a bridge bond, which is -CH 2 - or -CH 2 CH 2 -; each R 12 is independently H, C 1 - C 4 alkyl, C 1 -C 4 deuterated alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, Substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl; R 14 is C 1 -C 4 alkyl, C 1 -C 4 deuterated alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl or substituted or unsubstituted Monocyclic heteroaryl; R 15 is H or substituted or unsubstituted C 1 -C 6 alkyl; each R 16 is independently H, D, halogen, -CN, -OH, -N(R 15 ) 2. -NR 15 S(=O) 2 (C 1 -C 4 alkyl), -S(C 1 -C 4 alkyl), -S(=O) 2 (C 1 -C 4 alkyl), -C(=O)(C 1 -C 4 alkyl), -OC(=O)(C 1 -C 4 alkyl), -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -NR 15 C(=O)(C 1 -C 4 alkyl), -C(=O)N(R 15 ) 2 , -NR 15 C(=O)O(C 1 -C 4 alkyl), -OC(=O)N(R 15 ) 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 1 -C 4 deuterated alkyl, C 1 -C 4 deuterated alkoxy, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 heteroalkyl, substituted or unsubstituted Substituted C 3 -C 6 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heterocycloalkyl Aryl; n is 0, 1 or 2; R 17 is -L 5 -R 14 ; and L 5 does not exist, is -S(=O) 2 -, -C(=O)-, -CO 2 - or -C(=O)N(R 15 )-; wherein the term "substituted" means that the referenced group is substituted with one or more other groups independently selected from D, Halogen, -CN, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -OH, -CO 2 H, -CO 2 (C 1 -C 4 alkyl), -C(=O )NH 2 , -C(=O)NH(C 1 -C 4 alkyl), -C(=O)N(C 1 -C 4 alkyl) 2 , -S(=O) 2 NH 2 , - S(=O) 2 NH(C 1 -C 4 alkyl), -S(=O) 2 N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 3 -C 6 ring Alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, -SC 1 -C 4 alkyl, - S(=O)C 1 -C 4 alkyl and -S(=O) 2 C 1 -C 4 alkyl. 如請求項1之化合物或其醫藥學上可接受之鹽，其中： Y為-CR10R11-；R9為H；R11為H；或R9及R11一起形成橋鍵，其為-CH2CH2-；R4為H；R5為H；或R4及R5一起形成橋鍵，其為-CH2CH2-。 The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein: Y is -CR 10 R 11 -; R 9 is H; R 11 is H; or R 9 and R 11 together form a bridge, which is -CH 2 CH 2 -; R 4 is H; R 5 is H; or R 4 and R 5 together form a bridge, which is -CH 2 CH 2 -. 如請求項2之化合物或其醫藥學上可接受之鹽，其中：L不存在、為-O-、-S-、-CH2-、-CH2CH2-、-CH2O-、-OCH2-、-CH2NR15-、-NR15CH2-、-CH=CH-、-C≡C-、-C(=O)-、-C(=O)O-、-OC(=O)-、-OC(=O)O-、-C(=O)NR15-、-NR15C(=O)-、-OC(=O)NR15-、-NR15C(=O)O-、-NR15C(=O)NR15-、-NR15S(=O)2-、-NR15-、伸環丙基、伸環丁基或雙環[1.1.1]伸戊基。 The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein: L does not exist, is -O-, -S-, -CH 2 -, -CH 2 CH 2 -, -CH 2 O-, - OCH 2 -, -CH 2 NR 15 -, -NR 15 CH 2 -, -CH=CH-, -C≡C-, -C(=O)-, -C(=O)O-, -OC( =O)-, -OC(=O)O-, -C(=O)NR 15 -, -NR 15 C(=O)-, -OC(=O)NR 15 -, -NR 15 C(= O)O-, -NR 15 C(=O)NR 15 -, -NR 15 S(=O) 2 -, -NR 15 -, cyclopropyl, cyclobutyl or bicyclo[1.1.1] Amyl. 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中該化合物具有式(II)結構，或其醫藥學上可接受之鹽：
Figure 107108918-A0305-02-0189-2
 其中： R10為H、D、F、-CN、-OH、C1-C6烷基、C1-C6烷氧基、C1-C6氟烷基或-N(R12)2；X2為CR2；X3為CR3或N；各X4為CH；或各X4為N；或一個X4為N且另一個X4為CH。 A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound has a structure of formula (II), or a pharmaceutically acceptable salt thereof:
Figure 107108918-A0305-02-0189-2
 Where: R 10 is H, D, F, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkyl or -N(R 12 ) 2 X2 is CR2 ; X3 is CR3 or N; each X4 is CH; or each X4 is N; or one X4 is N and the other X4 is CH. 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中該化合物具有式(III)結構，或其醫藥學上可接受之鹽：
Figure 107108918-A0305-02-0190-3
 其中：R10為H、D、F、-CN、-OH、C1-C6烷基、C1-C6烷氧基、C1-C6氟烷基或-N(R12)2；X2為CR2；X3為CR3或N；各X4為CH；或各X4為N；或一個X4為N且另一個X4為CH。 A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt thereof:
Figure 107108918-A0305-02-0190-3
 Where: R 10 is H, D, F, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkyl or -N(R 12 ) 2 X2 is CR2 ; X3 is CR3 or N; each X4 is CH; or each X4 is N; or one X4 is N and the other X4 is CH. 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中該化合物具有式(IV)結構，或其醫藥學上可接受之鹽：
Figure 107108918-A0305-02-0191-4
 其中：R10為H、D、F、-CN、-OH、C1-C6烷基、C1-C6烷氧基、C1-C6氟烷基或-N(R12)2；X2為CR2；X3為CR3或N；各X4為CH；或各X4為N；或一個X4為N且另一個X4為CH。 A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound has a structure of formula (IV), or a pharmaceutically acceptable salt thereof:
Figure 107108918-A0305-02-0191-4
 Where: R 10 is H, D, F, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkyl or -N(R 12 ) 2 X2 is CR2 ; X3 is CR3 or N; each X4 is CH; or each X4 is N; or one X4 is N and the other X4 is CH. 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中該化合物具有式(V)結構，或其醫藥學上可接受之鹽：
Figure 107108918-A0305-02-0191-6
 其中：R10為H、D、F、-CN、-OH、C1-C6烷基、C1-C6烷氧基、C1-C6氟烷基或-N(R12)2；X2為CR2； X3為CR3或N；各X4為CH；或各X4為N；或一個X4為N且另一個X4為CH。 A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound has a structure of formula (V), or a pharmaceutically acceptable salt thereof:
Figure 107108918-A0305-02-0191-6
 Where: R 10 is H, D, F, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkyl or -N(R 12 ) 2 X2 is CR2 ; X3 is CR3 or N; each X4 is CH; or each X4 is N; or one X4 is N and the other X4 is CH. 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中：R1為H、D、F、Cl、-CN、-OH、-NH2、-NH(CH3)、-N(CH3)2、-NHS(=O)2CH3、-OC(=O)CH3、-CO2H、-CO2CH3、-NHC(=O)CH3、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3、-CH2CH(CH3)2、-C(CH3)3、-OCH3、-OCH2CH3、-OCH(CH3)2、-CD3、-OCD3、-CH2F、-CHF2、-CF3、-CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CF3、-CH2OH、-CH2OCH3、-CH2OCH2CH3、-CH2NH2、-CH2NHCH3或-CH2N(CH3)2；R2為H、D、F、Cl、-CN、-OH、-NH2、-NH(CH3)、-N(CH3)2、-NHS(=O)2CH3、-OC(=O)CH3、-CO2H、-CO2CH3、-NHC(=O)CH3、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3、-CH2CH(CH3)2、-C(CH3)3、-OCH3、-OCH2CH3、-OCH(CH3)2、-CD3、-OCD3、-CH2F、-CHF2、-CF3、-CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CF3、-CH2OH、-CH2OCH3、-CH2OCH2CH3、-CH2NH2、-CH2NHCH3或-CH2N(CH3)2；或R1及R2與插入原子一起形成經取代或未經取代之5員稠環，在該環中具有0至3個N原子及0至2個O或S原子，該環為經取代或未經取代之二氫呋喃基、經取代或未經取代之間二氧雜環戊烯基、經取代或未經取代之呋喃基、經取代或未經取代之噻吩基、經取代或未經取代之吡咯基、經取代或未經取代之噁唑基、經取代或未經取代之噻唑基、經取代或未經取代 之咪唑基、經取代或未經取代之吡唑基、經取代或未經取代之三唑基、經取代或未經取代之異噁唑基或經取代或未經取代之異噻唑基；R3為H、D、F、Cl、-CN、-OH、-SH、-NH2、-NH(CH3)、-N(CH3)2、-NHS(=O)2CH3、-OC(=O)CH3、-CO2H、-CO2CH3、-NHC(=O)CH3、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3、-CH2CH(CH3)2、-C(CH3)3、-OCH3、-OCH2CH3、-OCH(CH3)2、-CD3、-OCD3、-CH2F、-CHF2、-CF3、-CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CF3、-CH2OH、-CH2OCH3、-CH2OCH2CH3、-CH2NH2、-CH2NHCH3或-CH2N(CH3)2；R8為H、D、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3、-CH(CH3)CH2CH3、-CH2CH(CH3)2、-C(CH3)3、-CD3、-CH2F、-CHF2、-CF3、-CH2CF3、-CHFCH3、-CH2CH2F、-CH2CH2OH、-CH2CH2OCH3、-CH2CH2NH2、-CH2CH2NHCH3、-CH2CH2N(CH3)2、-C(=O)CH3、-C(=O)CH2CH3、-C(=O)CH(CH3)2、-CO2CH3、-CO2CH2CH3、-CO2CH(CH3)2、-C(=O)NHCH3、-S(=O)2CH3、-S(=O)2NHCH3、經取代或未經取代之環丙基、經取代或未經取代之環丁基、經取代或未經取代之環戊基、經取代或未經取代之環己基、經取代或未經取代之氧雜環丁烷基、經取代或未經取代之四氫呋喃基、經取代或未經取代之四氫哌喃基或經取代或未經取代之四氫硫代哌喃基；及各R16獨立地為H、D、F、Cl、-CN、-OH、-NH2、-NH(CH3)、-N(CH3)2、-NHS(=O)2CH3、-C(=O)CH3、-OC(=O)CH3、-CO2H、-CO2CH3、-NHC(=O)CH3、-CH3、-CH2CH3、-CH2CH2CH3、- CH(CH3)2、-CH2CH2CH2CH3、-CH2CH(CH3)2、-C(CH3)3、-CH=CH2、-CH=CHCH3、-C≡CH、-C≡CCH3、-C≡CCH2CH3、-OCH3、-OCH2CH3、-OCH(CH3)2、-S(=O)2CH3、-CD3、-OCD3、-CH2F、-CHF2、-CF3、-CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CF3、-CH2OH、-CH2CH2OH、-CH2OCH3、-CH2OCH2CH3、-CH2NH2、-CH2NHCH3或-CH2N(CH3)2、經取代或未經取代之環丙基、經取代或未經取代之環丁基、經取代或未經取代之環戊基、經取代或未經取代之環己基、經取代或未經取代之氮丙啶基、經取代或未經取代之氮雜環丁烷基、經取代或未經取代之吡咯啶基、經取代或未經取代之哌啶基、經取代或未經取代之四氫呋喃基、經取代或未經取代之四氫哌喃基、經取代或未經取代之四氫硫代哌喃基、經取代或未經取代之嗎啉基、經取代或未經取代之硫代嗎啉基或經取代或未經取代之哌嗪基。 A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein: R 1 is H, D, F, Cl, -CN, -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -NHS(=O) 2 CH 3 , -OC(=O)CH 3 , -CO 2 H, -CO 2 CH 3 , -NHC(=O)CH 3 , - CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 NH 2 , -CH 2 NHCH 3 , or -CH 2 N(CH 3 ) 2 ; R 2 is H, D, F, Cl, -CN, -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -NHS(=O) 2 CH 3 , -OC(=O)CH 3 , -CO 2 H, -CO 2 CH 3 , -NHC(=O)CH 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -OCH( CH 3 ) 2 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 NH 2 , -CH 2 NHCH 3 or -CH 2 N(CH 3 ) 2 ; or R 1 and R 2 with insertion Atoms taken together to form a substituted or unsubstituted 5-membered fused ring having 0 to 3 N atoms and 0 to 2 O or S atoms in the ring, the ring being a substituted or unsubstituted dihydrofuranyl , substituted or unsubstituted dioxolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or Unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, Substituted or unsubstituted isoxazolyl or substituted or unsubstituted isothiazolyl; R 3 is H, D, F, Cl, -CN, -OH, -SH, -NH 2 , -NH( CH 3 ), -N(CH 3 ) 2 , -NHS(=O) 2 CH 3 , -OC(=O)CH 3 , -CO 2 H, -CO 2 CH 3 , -NHC(=O)CH 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C( CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 NH 2 , -CH 2 NHCH 3 or -CH 2 N(CH 3 ) 2 ; R 8 is H, D, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , - CH 2 CF 3 , -CHFCH 3 , -CH 2 CH 2 F, -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)CH 2 CH 3 , -C(=O)CH(CH 3 ) 2 , -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 CH(CH 3 ) 2 , -C(=O)NHCH 3 , -S(=O) 2 CH 3 , -S(=O) 2 NHCH 3 , substituted or unsubstituted Substituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted oxetane substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl or substituted or unsubstituted tetrahydrothiopyranyl; and each R is independently H, D , F, Cl, -CN, -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -NHS(=O) 2 CH 3 , -C(=O)CH 3 , - OC(=O)CH 3 , -CO 2 H, -CO 2 CH 3 , -NHC(=O)CH 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH=CH 2 , -CH=CHCH 3 , -C≡CH, - C≡CCH 3 , -C≡CCH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -S(=O) 2 CH 3 , -CD 3 , -OCD 3 , - CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -CH 2 OH, -CH 2 CH 2 OH, - CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 NH 2 , -CH 2 NHCH 3 or -CH 2 N(CH 3 ) 2 , substituted or unsubstituted cyclopropyl, substituted or unsubstituted Substituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azacyclic Butyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted tetrahydrofuryl, substituted or unsubstituted tetrahydropyranyl, Substituted or unsubstituted tetrahydrothiopyranyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl or substituted or unsubstituted piperazinyl. 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中：R1為H、D、F、Cl、-CN、-OH、-NH2、-NH(CH3)、-N(CH3)2、-CH3、-CH2CH3、-OCH3、-OCH2CH3、-CD3、-OCD3、-CH2F、-CHF2、-CF3、-CH2CF3、-OCH2F、-OCHF2、-OCF3或-OCH2CF3；R2為H、D、F、Cl、-CH3、-CH2CH3、-OCH3、-OCH2CH3、-CD3、-OCD3、-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3或-OCH2CF3；R3為H、D、F、Cl、-CH3、-OCH3、-CD3、-OCD3、-CH2F、-CHF2、-CF3、-CH2CF3、-OCH2F、-OCHF2或-OCF3；R8為-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、- CH2CH2CH2CH3、-CH(CH3)CH2CH3、-CH2CH(CH3)2、-C(CH3)3、-CD3、-CH2F、-CHF2、-CF3、-CH2CF3、-CHFCH3、-CH2CH2F、-CH2CH2OH、-CH2CH2OCH3、-CH2CH2NH2、-CH2CH2NHCH3、-CH2CH2N(CH3)2、經取代或未經取代之環丙基、經取代或未經取代之環丁基、經取代或未經取代之環戊基、經取代或未經取代之環己基、經取代或未經取代之氧雜環丁烷基、經取代或未經取代之四氫呋喃基或經取代或未經取代之四氫哌喃基；及各R16獨立地為H、D、F、Cl、-CH3、-CH2CH3、-CD3、-CH2F、-CHF2、-CF3或-CH2CF3。 A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein: R 1 is H, D, F, Cl, -CN, -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 or -OCH 2 CF 3 ; R 2 is H, D, F, Cl, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 or -OCH 2 CF 3 ; R 3 is H, D, F, Cl, -CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -OCH 2 F , -OCHF 2 or -OCF 3 ; R 8 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCH 3 , -CH 2 CH 2 F, -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N(CH 3 ) 2 , substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl or substituted or unsubstituted tetrahydropyranyl; and each R 16 is independently H, D, F, Cl, -CH 3 , -CH2CH3 , -CD3 , -CH2F , -CHF2 , -CF3 , or -CH2CF3 . 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中：R1為-OH、-NH2、-NH(CH3)、-N(CH3)2、-CH3、-OCH3、-CD3、-OCD3、-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3或-OCH2CF3；R2為H、D、F、Cl、-CH3、-CD3、-CH2F、-CHF2或-CF3；R3為H。 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: R 1 is -OH, -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , - CH 3 , -OCH 3 , -CD 3 , -OCD 3 , -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 or -OCH 2 CF 3 ; R 2 is H, D, F, Cl, -CH3 , -CD3 , -CH2F , -CHF2 , or -CF3 ; R3 is H. 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中：
Figure 107108918-A0305-02-0195-7
為
Figure 107108918-A0305-02-0195-10
Figure 107108918-A0305-02-0195-11
或
Figure 107108918-A0305-02-0195-17
A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein:
Figure 107108918-A0305-02-0195-7
for
Figure 107108918-A0305-02-0195-10
Figure 107108918-A0305-02-0195-11
or
Figure 107108918-A0305-02-0195-17
 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中：
Figure 107108918-A0305-02-0196-13
為
Figure 107108918-A0305-02-0196-16
A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein:
Figure 107108918-A0305-02-0196-13
for
Figure 107108918-A0305-02-0196-16
 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中：m為0。 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: m is 0. 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中：n為0。 The compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: n is 0. 如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中：R10為-OH。 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: R 10 is -OH. 如請求項1之化合物或其醫藥學上可接受之鹽，其為：反-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N-(3-(4-甲基-1H-吡唑-1-基)苯基)環己烷甲醯胺；反-N-((反-4-(3-氰基-4-甲氧苯基)環己基)甲基)-N-(3-(1-乙基-1H-吡唑-4-基)苯基)-4-羥基環己烷甲醯胺；反-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N-(3-(1-甲基-1H-吡唑-4-基)苯基)環己烷甲醯胺；反-N-(3-(1-乙基-1H-吡唑-4-基)苯基)-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-N-((反-4-(3-氰基-4-甲氧苯基)環己基)甲基)-4-羥基-N-(3-(1-異丙 基-1H-吡唑-4-基)苯基)環己烷甲醯胺；反-N-((反-4-(3-氰基-4-甲氧苯基)環己基)甲基)-N-(3-(1-環丙基-1H-吡唑-4-基)苯基)-4-羥基環己烷甲醯胺；反-N-(3-(1-(2,2-二氟乙基)-1H-吡唑-4-基)苯基)-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N-(3-(1-(三氟甲基)-1H-吡唑-4-基)苯基)環己烷甲醯胺；反-N-(3-(1-環丙基-1H-吡唑-4-基)苯基)-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N-(3-(1-甲基-1H-吡唑-3-基)苯基)環己烷甲醯胺；反-4-羥基-N-(3-(1-異丙基-1H-吡唑-4-基)苯基)-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-4-羥基-N-(3-(1-異丁基-1H-吡唑-4-基)苯基)-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N-(3-(1-丙基-1H-吡唑-4-基)苯基)環己烷甲醯胺；反-4-羥基-N-(3-(1-(2-羥乙基)-1H-吡唑-4-基)苯基)-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-N-(3-(1-(2-(二甲胺基)乙基)-1H-吡唑-4-基)苯基)-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N-(3-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)苯基)環己烷甲醯胺； 反-N-(3-(1-環丁基-1H-吡唑-4-基)苯基)-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N-(3-(1-(氧雜環丁烷-3-基)-1H-吡唑-4-基)苯基)環己烷甲醯胺；反-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N-(3-(1-(四氫-2H-哌喃-4-基)-1H-吡唑-4-基)苯基)環己烷甲醯胺；反-N-(3-(1-(二氟甲基)-1H-吡唑-4-基)苯基)-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-N-(3-(1-(2-氟乙基)-1H-吡唑-4-基)苯基)-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-N-(3-(1-(第二丁基)-1H-吡唑-4-基)苯基)-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-N-(3-((1H-吡唑-4-基)乙炔基)苯基)-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N-(3-((1-甲基-1H-吡唑-3-基)乙炔基)苯基)環己烷甲醯胺；反-N-(3-((1H-吡唑-3-基)乙炔基)苯基)-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-N-(3-(1-環丙基-1H-吡唑-4-基)苯基)-N-((反-4-(3-氟-1-甲基-1H-吲唑-5-基)環己基)甲基)-4-羥基環己烷甲醯胺；反-4-羥基-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)-N-(3-(3-甲基-1H-吡唑-1-基)苯基)環己烷甲醯胺；反-N-(3-(1-環丙基-1H-吡唑-4-基)苯基)-N-((反-4-(6-(二甲胺基)吡啶 -3-基)環己基)甲基)-4-羥基環己烷甲醯胺；反-N-((反-4-(3-氯-4-甲氧苯基)環己基)甲基)-N-(3-(1-環丙基-1H-吡唑-4-基)苯基)-4-羥基環己烷甲醯胺；反-N-(3-(1-環丙基-1H-吡唑-4-基)苯基)-4-羥基-N-((4-(4-甲氧基-3-甲基苯基)雙環[2.2.2]辛烷-1-基)甲基)環己烷甲醯胺；反-4-胺基-N-(3-(1-異丙基-1H-吡唑-4-基)苯基)-N-((反-4-(4-甲氧基-3-甲基苯基)環己基)甲基)環己烷甲醯胺；反-4-胺基-N-(3-(1-環丙基-1H-吡唑-4-基)苯基)-N-((4-(4-甲氧基-3-甲基苯基)雙環[2.2.2]辛烷-1-基)甲基)環己烷甲醯胺；或其醫藥學上可接受之鹽。 Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, which is: trans-4-hydroxyl- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl) Methyl) -N- (3-(4-methyl- 1H -pyrazol-1-yl)phenyl)cyclohexanecarboxamide; trans- N -((trans-4-(3-cyano -4-methoxyphenyl)cyclohexyl)methyl) -N- (3-(1-ethyl- 1H -pyrazol-4-yl)phenyl)-4-hydroxycyclohexanecarboxamide; Trans-4-hydroxy- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl) -N- (3-(1-methyl-1 H -pyr Azol-4-yl)phenyl)cyclohexanecarboxamide; trans- N- (3-(1-ethyl- 1H -pyrazol-4-yl)phenyl)-4-hydroxy- N- ( (trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans- N -((trans-4-(3-cyano-4- Methoxyphenyl)cyclohexyl)methyl)-4-hydroxy- N- (3-(1-isopropyl- 1H -pyrazol-4-yl)phenyl)cyclohexanecarboxamide; trans- N -((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl) -N- (3-(1-cyclopropyl-1 H -pyrazol-4-yl) Phenyl)-4-hydroxycyclohexanecarboxamide; trans- N- (3-(1-(2,2-difluoroethyl)-1 H -pyrazol-4-yl)phenyl)-4 -Hydroxy- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-hydroxy- N -((trans- 4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl) -N- (3-(1-(trifluoromethyl)-1 H -pyrazol-4-yl)phenyl ) cyclohexanecarboxamide ; -methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-hydroxy- N -((trans-4-(4-methoxy-3-methyl phenyl)cyclohexyl)methyl) -N- (3-(1-methyl- 1H -pyrazol-3-yl)phenyl)cyclohexanecarboxamide; trans-4-hydroxy- N- ( 3-(1-isopropyl-1 H -pyrazol-4-yl)phenyl) -N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl ) cyclohexanecarboxamide; trans-4-hydroxy- N- (3-(1-isobutyl-1 H -pyrazol-4-yl)phenyl) -N -((trans-4-( -methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-hydroxy- N -((trans-4-(4-methoxy-3-methyl phenyl)cyclohexyl)methyl) -N- (3-(1-propyl- 1H -pyrazol-4-yl)phenyl)cyclohexanecarboxamide; trans-4-hydroxy- N- ( 3-(1-(2-Hydroxyethyl)-1 H -pyrazol-4-yl)phenyl) -N -((trans-4-(4-methoxy-3-methylphenyl)cyclo Hexyl)methyl)cyclohexanecarboxamide; trans- N- (3-(1-(2-(Dimethylamino)ethyl) -1H -pyrazol-4-yl)phenyl)-4 -Hydroxy- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-hydroxy- N -((trans- 4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl) -N- (3-(1-(2,2,2-trifluoroethyl)-1 H -pyrazole- 4-yl)phenyl)cyclohexanecarboxamide; trans- N- (3-(1-cyclobutyl- 1H -pyrazol-4-yl)phenyl)-4-hydroxy- N -(( trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-hydroxy- N -((trans-4-(4-methoxy Base-3-methylphenyl)cyclohexyl)methyl) -N- (3-(1-(oxetan-3-yl) -1H -pyrazol-4-yl)phenyl) ring Hexanecarboxamide; trans-4-hydroxy- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl) -N- (3-(1-( Tetrahydro- 2H -pyran-4-yl) -1H -pyrazol-4-yl)phenyl)cyclohexanecarboxamide; trans- N- (3-(1-(difluoromethyl) -1H -pyrazol-4-yl)phenyl)-4-hydroxy- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexane Formamide; trans- N- (3-(1-(2-fluoroethyl)-1 H -pyrazol-4-yl)phenyl)-4-hydroxy- N -((trans-4-(4 -Methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans- N- (3-(1-(Second-butyl) -1H -pyrazole-4- Base)phenyl)-4-hydroxy- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans- N- ( 3-(( 1H -pyrazol-4-yl)ethynyl)phenyl)-4-hydroxy- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl) Methyl)cyclohexanecarboxamide; trans-4-hydroxy- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl) -N- (3- ((1-Methyl-1 H -pyrazol-3-yl)ethynyl)phenyl)cyclohexanecarboxamide; trans- N- (3-((1 H -pyrazol-3-yl)ethynyl Base)phenyl)-4-hydroxy- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans- N- ( 3-(1-cyclopropyl-1 H -pyrazol-4-yl)phenyl) -N -((trans-4-(3-fluoro-1-methyl-1 H -indazol-5-yl )cyclohexyl)methyl)-4-hydroxycyclohexanecarboxamide; trans-4-hydroxy- N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)formazide Base) -N- (3-(3-methyl-1H-pyrazol-1-yl)phenyl)cyclohexanecarboxamide; trans- N- (3-(1-cyclopropyl-1 H- Pyrazol-4-yl)phenyl) -N -((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)-4-hydroxycyclohexanecarboxamide ; trans- N -((trans-4-(3-chloro-4-methoxyphenyl)cyclohexyl)methyl) -N- (3-(1-cyclopropyl- 1H -pyrazole-4- Base) phenyl)-4-hydroxycyclohexanecarboxamide; trans- N- (3-(1-cyclopropyl-1 H -pyrazol-4-yl)phenyl)-4-hydroxy- N- ((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide; trans-4-amino- N- (3-(1-isopropyl-1 H -pyrazol-4-yl)phenyl) -N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl base) cyclohexanecarboxamide; trans-4-amino- N- (3-(1-cyclopropyl-1 H -pyrazol-4-yl)phenyl) -N -((4-(4 -methoxy-3-methylphenyl)bicyclo[2.2.2]oct-1-yl)methyl)cyclohexanecarboxamide; or a pharmaceutically acceptable salt thereof. 如請求項1之化合物或其醫藥學上可接受之鹽，其具有下式結構：
Figure 107108918-A0305-02-0199-19
 或其醫藥學上可接受之鹽。 Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, which has the following structure:
Figure 107108918-A0305-02-0199-19
 or a pharmaceutically acceptable salt thereof. 一種醫藥組合物，其包含如請求項1至17中任一項之化合物或其醫藥學上可接受之鹽，及至少一種醫藥學上可接受之賦形劑。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 一種如請求項1至17中任一項之化合物或其醫藥學上可接受之鹽之用途，其係用於製造供治療或預防哺乳動物中之肝臟疾病或病狀、哺乳動物中之肝纖維化、哺乳動物中之肝炎、或哺乳動物中之胃腸道疾病或病狀的 藥劑。 A use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, for the manufacture of liver diseases or conditions in mammals, liver fibrosis in mammals Hepatitis in mammals, or gastrointestinal diseases or conditions in mammals potion. 如請求項19之用途，其中該肝臟疾病或病狀為原發性膽汁性肝硬化症、原發性硬化性膽管炎、膽汁鬱積、非酒精性脂肪變性肝炎(nonalcoholic steatohepatitis；NASH)、非酒精性脂肪肝病(nonalcoholic fatty liver disease；NAFLD)、脂肪肝(脂肪變性)、肝硬化症、酒精性肝炎、肝內膽汁鬱積或肝外膽汁鬱積；該肝纖維化係在經診斷患有C型肝炎病毒(hepatitis C virus；HCV)、非酒精性脂肪變性肝炎(NASH)、原發性硬化性膽管炎(primary sclerosing cholangitis；PSC)、肝硬化症、威爾遜氏病(Wilson's disease)、B型肝炎病毒(HBV)、HIV相關聯之脂肪變性肝炎及肝硬化症、慢性病毒性肝炎、非酒精性脂肪肝病(NAFLD)、酒精性脂肪變性肝炎(alcoholic steatohepatitis；ASH)、原發性膽汁性肝硬化症(primary biliary cirrhosis；PBC)或膽汁性肝硬化症之哺乳動物中；該肝炎係在經診斷患有C型肝炎病毒(HCV)、非酒精性脂肪變性肝炎(NASH)、原發性硬化性膽管炎(PSC)、肝硬化症、威爾遜氏病(Wilson's disease)、B型肝炎病毒(HBV)、HIV相關聯之脂肪變性肝炎及肝硬化症、慢性病毒性肝炎、非酒精性脂肪肝病(NAFLD)、酒精性脂肪變性肝炎(ASH)、原發性膽汁性肝硬化症(PBC)或膽汁性肝硬化症之哺乳動物中；該肝炎係在經診斷患有發炎性腸病之哺乳動物中；或該肝炎係與胃腸道中之炎症相關聯；該胃腸道疾病或病狀為壞死性小腸結腸炎、胃炎、潰瘍性結腸炎、克羅恩氏病(Crohn's disease)、發炎性腸病、大腸急躁症、胃腸炎、輻射 誘發腸炎、偽膜性結腸炎、化學療法誘發腸炎、胃-食道逆流病(gastro-esophageal reflux disease；GERD)、消化性潰瘍、非潰瘍性消化不良(non-ulcer dyspepsia；NUD)、乳糜瀉、腸道乳糜瀉、術後炎症、胃癌發生、移植物抗宿主疾病或其任何組合；或該胃腸疾病或病狀為伴隨腹瀉之大腸急躁症(IBS-D)、伴隨便秘之大腸急躁症(IBS-C)、混合型IBS(IBS-M)、未定型IBS(IBS-U)或膽汁酸腹瀉(BAD)。 Such as the use of claim 19, wherein the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic steatohepatitis (NASH), nonalcoholic nonalcoholic fatty liver disease (NAFLD), fatty liver (steatosis), cirrhosis, alcoholic hepatitis, intrahepatic cholestasis, or extrahepatic cholestasis; Hepatitis C virus (HCV), nonalcoholic steatosis hepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, Wilson's disease, hepatitis B virus (HBV), HIV-associated steatohepatitis and cirrhosis, chronic viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis ( primary biliary cirrhosis; PBC) or biliary cirrhosis in mammals diagnosed with hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, Wilson's disease, hepatitis B virus (HBV), HIV-associated steatosis and liver cirrhosis, chronic viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcohol in mammals with acute steatotic hepatitis (ASH), primary biliary cirrhosis (PBC), or biliary cirrhosis; in mammals diagnosed with inflammatory bowel disease; or in mammals Associated with inflammation in the gastrointestinal tract; the gastrointestinal disease or condition is necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel disorder, gastrointestinal inflammation, radiation Induced enteritis, pseudomembranous colitis, chemotherapy-induced enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease of the intestinal tract, postoperative inflammation, gastric carcinogenesis, graft versus host disease, or any combination thereof; or the gastrointestinal disease or condition is irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS- C), mixed IBS (IBS-M), unspecified IBS (IBS-U) or bile acid diarrhea (BAD).
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